WO2021076902A1 - INHIBITION DE L'INTÉGRINE α 4 β 7 HUMAINE - Google Patents

INHIBITION DE L'INTÉGRINE α 4 β 7 HUMAINE Download PDF

Info

Publication number
WO2021076902A1
WO2021076902A1 PCT/US2020/056001 US2020056001W WO2021076902A1 WO 2021076902 A1 WO2021076902 A1 WO 2021076902A1 US 2020056001 W US2020056001 W US 2020056001W WO 2021076902 A1 WO2021076902 A1 WO 2021076902A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
substituted
ethyl
unsubstituted
fluoro
Prior art date
Application number
PCT/US2020/056001
Other languages
English (en)
Inventor
Matthew G. Bursavich
Dan CUI
James E. Dowling
Kristopher N. HAHN
Bryce A. Harrison
Fu-Yang Lin
Blaise S. LIPPA
Bruce N. Rogers
Dawn M. TROAST
Cheng Zhong
Kyle D. KONZE
Aleksey I. GERASYUTO
Byungchan Kim
Salma RAFI
Tyler DAY
Eugene Hickey
Evelyne HOUANG
Robert Zahler
Original Assignee
Morphic Therapeutic, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Morphic Therapeutic, Inc. filed Critical Morphic Therapeutic, Inc.
Priority to JP2022509595A priority Critical patent/JP7437490B2/ja
Publication of WO2021076902A1 publication Critical patent/WO2021076902A1/fr
Priority to JP2024018765A priority patent/JP2024054293A/ja

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6

Definitions

  • TECHNICAL FIELD Disclosed are novel compounds and related methods useful for the inhibition of the ⁇ 4 ⁇ 7 integrin.
  • the compounds and methods disclosed herein are applicable to the development of medicaments for the treatment of ⁇ 4 ⁇ 7 integrin-mediated conditions, such as inflammatory bowel disease (IBD), ulcerative colitis (UC), and Crohn’s disease (CD).
  • IBD inflammatory bowel disease
  • UC ulcerative colitis
  • CD Crohn’s disease
  • BACKGROUND Integrins are noncovalently associated ⁇ / ⁇ heterodimeric cell surface receptors involved in numerous cellular processes.
  • integrins can regulate a cell's adhesive properties, allowing different leukocyte populations to be recruited to specific organs in response to different inflammatory signals.
  • the ⁇ 4 integrins include ⁇ 4 ⁇ 7 , play a role in lymphocyte migration throughout the gastrointestinal tract. They are expressed on most leukocytes, including B and T lymphocytes, where they mediate cell adhesion via selective binding to its primary ligand, mucosal addressin cell adhesion molecule (MAdCAM).
  • MAdCAM mucosal addressin cell adhesion molecule
  • Memory T lymphocytes expressing the ⁇ 4 ⁇ 7 integrin preferentially migrate into the gastrointestinal tract via firm adhesion to mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1).
  • Inhibitors of specific integrin-ligand interactions have been used for the treatment of various diseases.
  • monoclonal antibodies displaying high binding affinity for ⁇ 4 ⁇ 7 have displayed therapeutic benefits for gastrointestinal auto-inflammatory/autoimmune diseases, such as Crohn's disease, and ulcerative colitis.
  • these therapies also have certain undesirable properties for the patient.
  • a monoclonal antibody ⁇ 4 ⁇ 7 integrin inhibitor is administered by parenteral administration, has a long half-life with inability to rapidly modify exposures, and a reduced activity due to anti-drug antibody formation.
  • Monoclonal antibody therapies can be challenging to manufacture in comparison to small molecule therapies.
  • the invention relates to compounds of Formula (I): wherein R a , R b , and R c are independently selected from the group consisting of H, Me, halide, CF 3 , C(H)F 2 , C(F)H 2 , -CN, - OCF 3 , substituted or unsubstituted (C 1 -C 5 )-alkyl, substituted or unsubstituted (C 1 -C 5 )-alkoxy, -CH 2 CF 3, and substituted or unsubstituted –(C 1- C 5 )alkylene-N- (R x )(R y ); provided that at least one of R a , R b , and R c is –(C 1 -C 5 )alkylene-N-(R x )(R y ); R x and R y are independently selected from the group consisting of H and substituted or unsubstituted (C
  • a compound of Formula (I) can be a compound wherein one and only one of R a , R b , and R c is substituted or unsubstituted -(C 1 -C 5 )alkylene-N- (R x )(R y );
  • R 1 is (C 1 -C 6 ) alkyl (e.g., isobutyl);
  • R3a and R3b are independently selected from the group consisting of H, (C 1 -C 4 )-alkyl (e.g., methyl), halide (e.g., F or Cl), CF 3 , C(H)F 2 , and C(F)H 2 , provided that R 3a and R 3b are not both H; and R 4 is H.
  • a compound of Formula (I) can be a compound wherein one and only one of R a , R b , and R c is substituted or unsubstituted -(C 1 -C 5 )alkylene-N-(R x )(R y ); R x and R y are each independently unsubstituted (C 1 -C 6 )-alkyl (e.g., methyl) or R x and R y taken together with the N to which they are attached form a substituted or unsubstituted 4-6 membered heterocyclyl ring; R 1 is unsubstituted (C 1 -C 6 ) alkyl (e.g., isobutyl); R3a and R3b are independently selected from the group consisting of H, unsubstituted (C 1 -C 4 )-alkyl (e.g., methyl, ethyl, etc.), halide (e.g., F
  • a compound of Formula (I), Formula (Ia) and/or Formula (Ib) can be a compound wherein one and only one of R a , R b , and R c is substituted or unsubstituted -(C 1 -C 5 )alkylene-N-(R x )(R y ); R x and R y each independently unsubstituted methyl or R x and R y taken together with the N to which they are attached form a substituted or unsubstituted 4-6 membered heterocyclyl ring; R 1 is is isobutyl; R 3a and R 3b are independently selected from the group consisting of unsubstituted (C 1 -C 4 )-alkyl (e.g., methyl), halide (e.g., F or Cl), CF 3 , C(H)F 2 , and C(F)H 2 , R 3c and R 3d are both H; and R 4 is H.
  • a compound of Formula (I), Formula (Ia) and/or Formula (Ib) can be a compound wherein R 1 is isobutyl; R 3a and R 3b are independently selected from the group consisting of unsubstituted (C 1 -C 4 )-alkyl (e.g., methyl), halide (e.g., F or Cl), CF 3 , C(H)F 2 , and C(F)H 2 , R 3c and R 3d are both H; R 4 is H; and R 5a , and R 5e are each substituted or unsubstituted (C 1 -C 4 )-alkyl (e.g., methyl).
  • R 1 is isobutyl
  • R 3a and R 3b are independently selected from the group consisting of unsubstituted (C 1 -C 4 )-alkyl (e.g., methyl), halide (e.g., F or Cl), CF 3 , C(H)F
  • a compound of Formula (I) can be a compound wherein one and only one of R a , R b , and R c is substituted or unsubstituted -(C 1 -C 5 )alkylene-N-(R x )(R y ); R x and R y each independently unsubstituted methyl or R x and R y taken together with the N to which they are attached form a 4-6 membered heterocyclyl ring optionally substituted with halide (e.g., F); R 1 is isobutyl; R3a and R3b are independently selected from the group consisting of unsubstituted (C 1 -C 4 )-alkyl (e.g., methyl), halide (e.g., F or Cl), CF 3 , C(H)F 2 , and C(F)H 2 , R 3c and R 3d are both H; R 4 is H; R 5a , and R 5e are each substituted
  • Figure 1 is a table (Table 1) summarizing in vitro inhibition of ⁇ 4 ⁇ 7 integrin by exemplary compounds (i.e., data obtained from the fluorescence polarization assay of Example 5, and the ligand binding assay of Example 6).
  • Figure 2 is a table (Table 2) providing additional exemplary compounds.
  • DETAILED DESCRIPTION In certain embodiments, the invention relates to compounds that antagonize ⁇ 4 ⁇ 7 integrin.
  • an element means one element or more than one element.
  • the phrase “and/or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and/or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined.
  • references to “A and/or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.
  • “or” should be understood to have the same meaning as “and/or” as defined above.
  • the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e., “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law.
  • the phrase “at least one,” in reference to a list of one or more elements should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements.
  • At least one of A and B can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.
  • compositions of the present invention may exist in particular geometric or stereoisomeric forms.
  • polymers of the present invention may also be optically active.
  • the present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)- isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention. If, for instance, a particular enantiomer of compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
  • Structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds produced by the replacement of a hydrogen with deuterium or tritium, or of a carbon with a 13 C- or 14 C- enriched carbon are within the scope of this invention.
  • ⁇ 4 ⁇ 7 means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject chemical from one organ or portion of the body, to another organ or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, not injurious to the patient, and substantially non- pyrogenic.
  • materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alg
  • compositions of the present invention are non-pyrogenic, i.e., do not induce significant temperature elevations when administered to a patient.
  • pharmaceutically acceptable salts refers to the relatively non-toxic, inorganic and organic acid addition salts of the compound(s). These salts can be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting a purified compound(s) in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and the like.
  • sulfate bisulfate
  • phosphate nitrate
  • acetate valerate
  • oleate palmitate
  • stearate laurate
  • benzoate lactate
  • phosphate tosylate
  • citrate maleate
  • fumarate succinate
  • tartrate naphthylate
  • mesylate glucoheptonate
  • lactobionate lactobionate
  • laurylsulphonate salts and the like.
  • the compounds useful in the methods of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases.
  • pharmaceutically acceptable salts refers to the relatively non-toxic inorganic and organic base addition salts of a compound(s). These salts can likewise be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting the purified compound(s) in its free acid form with a suitable base, such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, or tertiary amine.
  • Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like (see, for example, Berge et al., supra).
  • a “therapeutically effective amount” (or “effective amount”) of a compound with respect to use in treatment refers to an amount of the compound in a preparation which, when administered as part of a desired dosage regimen (to a mammal, preferably a human) alleviates a symptom, ameliorates a condition, or slows the onset of disease conditions according to clinically acceptable standards for the disorder or condition to be treated or the cosmetic purpose, e.g., at a reasonable benefit/risk ratio applicable to any medical treatment.
  • a desired dosage regimen to a mammal, preferably a human
  • the term “prophylactic or therapeutic” treatment is art-recognized and includes administration to the host of one or more of the subject compositions.
  • the treatment is prophylactic, (i.e., it protects the host against developing the unwanted condition), whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).
  • the term “patient” refers to a mammal in need of a particular treatment.
  • a patient is a primate, canine, feline, or equine.
  • a patient is a human.
  • An aliphatic chain comprises the classes of alkyl, alkenyl and alkynyl defined below.
  • a straight aliphatic chain is limited to unbranched carbon chain moieties.
  • the term “aliphatic group” refers to a straight chain, branched-chain, or cyclic aliphatic hydrocarbon group and includes saturated and unsaturated aliphatic groups, such as an alkyl group, an alkenyl group, or an alkynyl group.
  • “Alkyl” refers to a fully saturated cyclic or acyclic, branched or unbranched carbon chain moiety having the number of carbon atoms specified, or 1 up to 30 carbon atoms if no specification is made.
  • alkyl of 1 to 8 carbon atoms refers to moieties such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, and those moieties which are positional isomers of these moieties.
  • Alkyl of 10 to 30 carbon atoms includes decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl and tetracosyl.
  • a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chains, C3-C30 for branched chains), and more preferably 20 or fewer.
  • Alkyl goups may be substituted or unsubstituted.
  • “Me” and –CH 3 both refer to methyl.
  • the term “alkylene” refers to an alkyl group having the specified number of carbons, for example from 2 to 12 carbon atoms, that contains two points of attachment to the rest of the compound on its longest carbon chain.
  • alkylene groups include methylene -(CH 2 )-, ethylene -(CH 2 CH 2 )-, n-propylene - (CH 2 CH 2 CH 2 )-, isopropylene -(CH 2 CH(CH3))-, and the like.
  • Alkylene groups can be cyclic or acyclic, branched or unbranched carbon chain moiety, and may be optionally substituted with one or more substituents.
  • Cycloalkyl means mono- or bicyclic or bridged or spirocyclic, or polycyclic saturated carbocyclic rings, each having from 3 to 12 carbon atoms. Likewise, preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 3-6 carbons in the ring structure. Cycloalkyl groups may be substituted or unsubstituted.
  • lower alkyl means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.
  • lower alkenyl and “lower alkynyl” have similar chain lengths.
  • preferred alkyl groups are lower alkyls.
  • a substituent designated herein as alkyl is a lower alkyl.
  • aryl as used herein includes 3- to 12-membered substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon (i.e., carbocyclic aryl) or where one or more atoms are heteroatoms (i.e., heteroaryl).
  • aryl groups include 5- to 12-membered rings, more preferably 6- to 10-membered rings
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Carbocyclic aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.
  • Heteroaryl groups include substituted or unsubstituted aromatic 3- to 12- membered ring structures, more preferably 5- to 12-membered rings, more preferably 5- to 10- membered rings, whose ring structures include one to four heteroatoms.
  • Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like.
  • Aryl and heteroaryl can be monocyclic, bicyclic, or polycyclic.
  • halo means halogen and includes, for example, and without being limited thereto, fluoro, chloro, bromo, iodo and the like, in both radioactive and non-radioactive forms. In a preferred embodiment, halo is selected from the group consisting of fluoro, chloro and bromo.
  • heterocyclyl or “heterocyclic group” refer to 3- to 12-membered ring structures, more preferably 5- to 12-membered rings, more preferably 5- to 10-membered rings, whose ring structures include one to four heteroatoms. Heterocycles can be monocyclic, bicyclic, spirocyclic, or polycyclic.
  • Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, o
  • the heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF 3 , -CN, and the like.
  • substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino
  • carbonyl is art-recognized and includes such moieties as can be represented by the formula: wherein X’ is a bond or represents an oxygen or a sulfur, and R 1 5 represents a hydrogen, an alkyl, an alkenyl, -(CH 2 )m-R 1 0 or a pharmaceutically acceptable salt, R 1 6 represents a hydrogen, an alkyl, an alkenyl or -(CH 2 ) m -R 10 , where m and R 10 are as defined above.
  • substituted is contemplated to include all permissible substituents of organic compounds.
  • permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, for example, those described herein above, and for example substituted with one or more substituents selected from alkyl, cycloalkyl, heterocyclylakyl, halogen, OH, OMe, C(H)F 2 , C(F)H 2 , CF 3 , C(H) 2 CF 3 , SF 5 , CHFCH 2 amine, CH 2 amine, and CN.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • nitro means -NO 2
  • halogen designates - F, -Cl, -Br, or -I
  • hydroxyl means -OH
  • cyano means –CN;
  • prodrug as used herein encompasses compounds that, under physiological conditions, are converted into therapeutically active agents.
  • a common method for making a prodrug is to include selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule.
  • the prodrug is converted by an enzymatic activity of the host animal.
  • the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover. EXEMPLARY COMPOUNDS
  • the invention relates to a compound of Formula (I), Formula (Ia), or Formula (Ib):
  • R a , R b , and R c are independently selected from the group consisting of H, Me, halide, CF 3 , C(H)F 2 , C(F)H 2 , -CN, - OCF 3 , substituted or unsubstituted (C 1 -C 5 )-alkyl, substituted or unsubstituted (C 1 -C 5 )-alkoxy, -CH 2 CF 3 , and substituted or unsubstituted –(C 1 -C 5 )alkylene-N- (R x )(R y ); provided that at least one of R a , R b , and R c is –(C 1 -C 5 )alkylene-N-(R x )(R y ); R x and R y are independently selected from the group consisting of H and substituted or unsubstituted (C 1 -C 6 )-
  • a compound of Formula (I) can be a compound of Formula (Ia), Formula (Ib), Formula (Ic) and/or Formula (Id): wherein R a , R b , R c , R 1 , R3a, R3b, R 3c , R 3d , R5a, R5b, R5c, R 5d , R5e, and R 4 in Formula (Ia), Formula (Ib), Formula (Ic) and Formula (Id) are each independently defined as above with respect to Formula (I).
  • a compound of Formula (I) can be a compound of Formula (II), including compounds of Formula (IIa), Formula (IIb) or Formula (IIc):
  • R a , R c , R 3a , R 3b , R 3c , R 3d , R 5a , R 5b , R 5c , R 5d , and R 5e are as described in Formula (I); p is 1, 2, or 3; q is 0, 1, 2 or 3; r is an 0, 1, 2, 3 or 4; s is 0, 1, 2, 3, 4 or 5; and each Rd is independently selected from the group consisting of halide, (C 1 -C 5 )-alkyl, (C 1 -C 4 )-alkoxy, - CF 3 , -C(H)F 2 , -OCF 3 , and -CN.
  • At least one instance of Rd is F or Cl. In some embodiments, at least one instance of R d is methyl. In some embodiments, at least one instance of R d is methoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds of Formula (IIa), wherein q is 1. In certain embodiments, the invention relates to any one of the aforementioned compounds of Formula (IIb), wherein r is 1. In certain embodiments, the invention relates to any one of the aforementioned compounds of Formula (IIc), wherein s is 1. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 1 is unsubstituted (C 1 -C 6 )-alkyl.
  • the invention relates to any one of the aforementioned compounds, wherein R 1 is substituted (C 1 -C 6 )-alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 1 is substituted or unsubstituted (C 1 -C 4 )-alkyl. In certain embodiments, R 1 is methyl, ethyl, isopropyl, n-propyl, i-butyl, n-butyl, sec-butyl, or t-butyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 1 is selected from the group consisting of and .
  • the invention relates to any one of the aforementioned compounds, wherein R 1 is substituted (C 1 -C 4 )-alkylene-(C 3 -C 6 )-cycloalkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 1 is unsubstituted (C 1 -C 4 )-alkylene-(C 3 -C 6 )-cycloalkyl. In certain embodiments, R 1 is . In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 1 is substituted (C 1 -C 4 )-alkylene- (C 1 -C 4 )-alkoxy.
  • the invention relates to any one of the aforementioned compounds, wherein R 1 is unsubstituted (C 1 -C 4 )-alkylene- (C 1 -C 4 )-alkoxy. In certain embodiments, R 1 is In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 3a is H; provided that R 3a and R 3b are not both H. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R3a is unsubstituted (C 1 -C 4 )-alkyl.
  • the invention relates to any one of the aforementioned compounds, wherein R 3a is substituted (C 1 -C 4 )-alkyl. In certain embodiments, the substituted (C 1 -C 5 )-alkyl, is substituted with a halogen. In certain embodiments, the halogen is Cl or F. In certain embodiments, R3a is methyl, ethyl, isopropyl, n-propyl, i-butyl, n-butyl, or t-butyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 3a is substituted (C 3 -C 6 )-cycloalkyl.
  • the invention relates to any one of the aforementioned compounds, wherein R3a is substituted or unsubstituted (C 3 -C 6 )-cycloalkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R3a is cyclopropyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R3a is halide. In some embodiments, the halide is Cl or F. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R3a is CF 3 . In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 3a is C(H)F 2 .
  • the invention relates to any one of the aforementioned compounds, wherein R3a is C(F)H 2 . In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 3a is substituted -(C 1 -C 4 )-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R3a is unsubstituted -(C 1 -C 4 )-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R3a is -OCF 3 .
  • the invention relates to any one of the aforementioned compounds, wherein R 3a is substituted (C 1 -C 4 )-alkylene-(C 1 -C 4 )-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R3a is unsubstituted (C 1 -C 4 )-alkylene-(C 1 -C 4 )- alkoxy. In certain embodiments, (C 1 -C 4 )-alkylene-(C 1 -C 4 )-alkoxy is –CH 2 OMe.
  • the invention relates to any one of the aforementioned compounds, wherein R3b is H; provided that R3a and R3b are not both H. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 3b is unsubstituted (C 1 -C 4 )-alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R3b is substituted (C 1 -C 4 )-alkyl. In certain embodiments, the substituted (C 1 -C 5 )-alkyl, is substituted with a halogen. In certain embodiments, the halogen is Cl or F.
  • R 3b is methyl, ethyl, isopropyl, n-propyl, i-butyl, n-butyl, or t-butyl.
  • the invention relates to any one of the aforementioned compounds, wherein R3b is substituted (C 3 -C 6 )-cycloalkyl.
  • the invention relates to any one of the aforementioned compounds, wherein R3b is substituted or unsubstituted (C 3 -C 6 )-cycloalkyl.
  • the invention relates to any one of the aforementioned compounds, wherein R3b is cyclopropyl.
  • the invention relates to any one of the aforementioned compounds, wherein R 3b is halide. In some embodiments, the halide is Cl or F. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R3b is CF 3 . In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 3b is C(H)F 2 . In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R3b is C(F)H 2 . In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R3b is substituted -(C 1 -C 4 )-alkoxy.
  • the invention relates to any one of the aforementioned compounds, wherein R3b is unsubstituted -(C 1 -C 4 )-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R3b is -OCF 3 . In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 3b is substituted (C 1 -C 4 )-alkylene-(C 1 -C 4 )-alkoxy.
  • the invention relates to any one of the aforementioned compounds, wherein R3b is unsubstituted (C 1 -C 4 )-alkylene-(C 1 -C 4 )- alkoxy.
  • (C 1 -C 4 )-alkylene-(C 1 -C 4 )-alkoxy is –CH 2 OMe.
  • R 3a and R 3b are independently selected from the group consisting of H, (C 1 -C 5 )-alkyl, halide, CF 3 , C(H)F 2 , and C(F)H 2 ; provided that R3a and R3b are not both H.
  • R3a and R3b can be independently selected from the group consisting of H, methyl, Cl, F, CF 3 , C(H)F 2 , and C(F)H 2 ; provided that R 3a and R 3b are not both H.
  • the invention relates to any one of the aforementioned compounds, wherein R 3c is selected from the group consisting of: H, substituted or unsubstituted (C 1 -C 5 )-alkyl, substituted or unsubstituted cyclopropyl, hydroxyl, methoxy, halide, CF 3 , C(H)F 2 , C(F)H 2 , and –CN.
  • the invention relates to any one of the aforementioned compounds, wherein R 3c is H. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 3c is unsubstituted (C 1 -C 4 )-alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 3c is substituted (C 1 -C 4 )-alkyl. In certain embodiments, the substituted (C 1 -C 5 )-alkyl, is substituted with a halogen. In certain embodiments, the halogen is Cl or F.
  • R 3c is methyl, ethyl, isopropyl, n-propyl, i-butyl, n-butyl, or t-butyl.
  • the invention relates to any one of the aforementioned compounds, wherein R 3c is substituted (C 3 -C 6 )-cycloalkyl.
  • the invention relates to any one of the aforementioned compounds, wherein R 3c is substituted or unsubstituted (C3- C6)-cycloalkyl.
  • the invention relates to any one of the aforementioned compounds, wherein R 3c is cyclopropyl.
  • the invention relates to any one of the aforementioned compounds, wherein R 3c is halide. In some embodiments, the halide is Cl or F. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 3c is CF 3 . In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 3c is C(H)F 2 . In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 3c is C(F)H 2 . In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 3c is substituted -(C 1 -C 4 )-alkoxy.
  • the invention relates to any one of the aforementioned compounds, wherein R 3c is unsubstituted - (C 1 -C 4 )-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 3c is -OCF 3 . In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 3c is substituted (C 1 -C 4 )- alkylene-(C 1 -C 4 )-alkoxy.
  • the invention relates to any one of the aforementioned compounds, wherein R 3c is unsubstituted (C 1 -C 4 )-alkylene-(C 1 -C 4 )-alkoxy.
  • (C 1 -C 4 )-alkylene-(C 1 -C 4 )-alkoxy is –CH 2 OMe.
  • the invention relates to any one of the aforementioned compounds, wherein R 3d is selected from the group consisting of H, substituted or unsubstituted (C 1 -C 5 )-alkyl, hydroxyl, halide, methoxy, halide, CF 3 , C(H)F 2 , and C(F)H 2 .
  • R 3d is selected from the group consisting of H, substituted or unsubstituted (C 1 -C 5 )-alkyl, hydroxyl, halide, methoxy, halide, CF 3 , C(H)F 2 , and C(F)H 2 .
  • the invention relates to any one of the aforementioned compounds, wherein R 3d H.
  • the invention relates to any one of the aforementioned compounds, wherein R 3d is unsubstituted (C 1 -C 4 )-alkyl.
  • the invention relates to any one of the aforementioned compounds, wherein R 3d is substituted (C 1 -C 4 )-alkyl. In certain embodiments, the substituted (C 1 -C 5 )-alkyl, is substituted with a halogen. In certain embodiments, the halogen is F. In certain embodiments, R 3d is methyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 3d is substituted (C 3 -C 6 )-cycloalkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 3c is substituted or unsubstituted (C 3 -C 6 )-cycloalkyl.
  • the invention relates to any one of the aforementioned compounds, wherein R 3d is cyclopropyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 3d is halide. In some embodiments, the halide is Cl or F. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 3d is CF 3 . In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 3d is C(H)F 2 . In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 3d is C(F)H 2 .
  • the invention relates to any one of the aforementioned compounds, wherein R 3d is substituted -(C 1 -C 4 )-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 3d is unsubstituted - (C 1 -C 4 )-alkoxy. In certain embodiments, -(C 1 -C 4 )-alkoxy is methoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 3d is -OCF 3 .
  • the invention relates to any one of the aforementioned compounds, wherein R 3d is substituted (C 1 -C 4 )-alkylene-(C 1 -C 4 )-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 3d is unsubstituted (C 1 -C 4 )-alkylene-(C 1 -C 4 )-alkoxy. In certain embodiments, (C 1 -C 4 )- alkylene-(C 1 -C 4 )-alkoxy is –CH 2 OMe. In some embodiments, R 3c and R 3d are the same. In some embodiments, R 3c and R 3d are different.
  • R 3c and R 3d are both H.
  • the invention relates to any one of the aforementioned compounds, wherein R 4 is H.
  • the invention relates to any one of the aforementioned compounds, wherein R 4 is substituted (C 1 -C 4 )-alkyl.
  • the invention relates to any one of the aforementioned compounds, wherein R 4 is unsubstituted (C 1 -C 4 )-alkyl.
  • the invention relates to any one of the aforementioned compounds, wherein R 4 is methyl, ethyl, n-propyl, or i-propyl.
  • the invention relates to any one of the aforementioned compounds, wherein R 4 is methyl or ethyl.
  • R5a is H.
  • the invention relates to any one of the aforementioned compounds, wherein R5a is substituted or unsubstituted (C 1 -C 4 )- alkyl.
  • the invention relates to any one of the aforementioned compounds, wherein R 5a is unsubstituted (C 1 -C 4 )-alkyl.
  • the invention relates to any one of the aforementioned compounds, wherein R5a is substituted (C 1 -C 4 )-alkyl.
  • the substituted (C 1 -C 5 )-alkyl is substituted with one or more halogen.
  • the halogen is Cl or F.
  • R 5a is methyl, ethyl, isopropyl, n-propyl, i-butyl, n-butyl, or t-butyl.
  • the invention relates to any one of the aforementioned compounds, wherein R5a is halide.
  • the halide is Cl or F.
  • R 5a is substituted (C 3 -C 6 )- cycloalkyl.
  • R5a is unsubstituted (C 3 -C 6 )-cycloalkyl. In some embodiments, (C 3 -C 6 )-cycloalkyl is cyclopropyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5a is CF 3 . In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5a is C(H)F 2 . In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5a is C(F)H 2 .
  • the invention relates to any one of the aforementioned compounds, wherein R5a is (C 1 -C 4 )-alkoxy. In some embodiments, (C 1 -C 4 )-alkoxy is methoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5a is methoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R5a is hydroxyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5a is –OCF 3. In certain embodiments, R 5a is CN.
  • the invention relates to any one of the aforementioned compounds, wherein R 5a is substituted (C 1 -C 4 )- alkylene-(C 1 -C 4 )-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5a is unsubstituted (C 1 -C 4 )-alkylene-(C 1 -C 4 )-alkoxy. In certain embodiments, (C 1 -C 4 )-alkylene-(C 1 -C 4 )-alkoxy is –CH 2 OMe. In certain embodiments, R5a is CH 2 OH.
  • the invention relates to any one of the aforementioned compounds, wherein R 5b is CN. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R5b is unsubstituted (C 1 -C 4 )-alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5b is substituted (C 1 -C 4 )-alkyl. In certain embodiments, the substituted (C 1 -C 5 )-alkyl, is substituted with a halogen. In certain embodiments, the halogen is Cl or F.
  • R5b is methyl, ethyl, isopropyl, n-propyl, i-butyl, n-butyl, or t-butyl.
  • the invention relates to any one of the aforementioned compounds, wherein R 5b is halide.
  • the halide is Cl or F.
  • R 5b is substituted (C 3 -C 6 )-cycloalkyl.
  • R5b is unsubstituted (C 3 -C 6 )- cycloalkyl.
  • the invention relates to any one of the aforementioned compounds, wherein R 5b is CF 3 .
  • the invention relates to any one of the aforementioned compounds, wherein R5b is C(H)F 2 . In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R5b is C(F)H 2 . In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R5b is (C 1 -C 4 )-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R5b is methoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5b is hydroxyl.
  • the invention relates to any one of the aforementioned compounds, wherein R5b is –OCF 3 . In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5b is substituted (C 1 -C 4 )-alkylene-(C 1 -C 4 )-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R5b is unsubstituted (C 1 -C 4 )-alkylene-(C 1 -C 4 )-alkoxy. In certain embodiments, (C 1 -C 4 )- alkylene-(C 1 -C 4 )-alkoxy is –CH 2 OMe.
  • the invention relates to any one of the aforementioned compounds, wherein R5c is CN. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R5c is unsubstituted (C 1 -C 4 )-alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5c is substituted (C 1 -C 4 )-alkyl. In certain embodiments, the substituted (C 1 -C 5 )-alkyl, is substituted with a halogen. In certain embodiments, the halogen is Cl or F.
  • R 5c is methyl, ethyl, isopropyl, n-propyl, i-butyl, n-butyl, or t-butyl.
  • the invention relates to any one of the aforementioned compounds, wherein R5c is halide.
  • the halide is Cl or F.
  • R5c is substituted (C 3 -C 6 )-cycloalkyl.
  • R5c is unsubstituted (C 3 -C 6 )- cycloalkyl.
  • the invention relates to any one of the aforementioned compounds, wherein R5c is CF 3 .
  • the invention relates to any one of the aforementioned compounds, wherein R5c is C(H)F 2 . In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5c is C(F)H 2 . In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R5c is (C 1 -C 4 )-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5c is methoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5c is hydroxyl.
  • the invention relates to any one of the aforementioned compounds, wherein R 5c is –OCF 3. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5c is substituted (C 1 -C 4 )-alkylene-(C 1 -C 4 )-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R5c is unsubstituted (C 1 -C 4 )-alkylene-(C 1 -C 4 )-alkoxy. In certain embodiments, (C 1 -C 4 )- alkylene-(C 1 -C 4 )-alkoxy is –CH 2 OMe.
  • the invention relates to any one of the aforementioned compounds, wherein R 5d is CN. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5d is unsubstituted (C 1 -C 4 )-alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5d is substituted (C 1 -C 4 )-alkyl. In certain embodiments, the substituted (C 1 -C 5 )-alkyl, is substituted with a halogen. In certain embodiments, the halogen is Cl or F.
  • R 5d is methyl, ethyl, isopropyl, n-propyl, i-butyl, n-butyl, or t-butyl.
  • the invention relates to any one of the aforementioned compounds, wherein R 5d is halide.
  • the halide is Cl or F.
  • R 5d is substituted (C 3 -C 6 )-cycloalkyl.
  • R 5d is unsubstituted (C 3 -C 6 )- cycloalkyl.
  • the invention relates to any one of the aforementioned compounds, wherein R 5d is CF 3 .
  • the invention relates to any one of the aforementioned compounds, wherein R 5d is C(H)F 2 . In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5d is C(F)H 2 . In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5d is (C 1 -C 4 )-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5d is methoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5d is hydroxyl.
  • the invention relates to any one of the aforementioned compounds, wherein R 5d is –OCF 3 . In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5d is substituted (C 1 -C 4 )-alkylene-(C 1 -C 4 )-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5d is unsubstituted (C 1 -C 4 )-alkylene-(C 1 -C 4 )-alkoxy. In certain embodiments, (C 1 -C 4 )- alkylene-(C 1 -C 4 )-alkoxy is –CH 2 OMe.
  • the invention relates to any one of the aforementioned compounds, wherein R 5e is CN. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R5e is unsubstituted (C 1 -C 4 )-alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5e is substituted (C 1 -C 4 )-alkyl. In certain embodiments, the substituted (C 1 -C 5 )-alkyl, is substituted with a halogen. In certain embodiments, the halogen is Cl or F.
  • R5e is methyl, ethyl, isopropyl, n-propyl, i-butyl, n-butyl, or t-butyl.
  • the invention relates to any one of the aforementioned compounds, wherein R5e is halide.
  • the halide is Cl or F.
  • R5e is substituted (C 3 -C 6 )-cycloalkyl.
  • R5e is unsubstituted (C 3 -C 6 )- cycloalkyl.
  • the invention relates to any one of the aforementioned compounds, wherein R 5e is CF 3 .
  • the invention relates to any one of the aforementioned compounds, wherein R5e is C(H)F 2 . In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5e is C(F)H 2 . In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R5e is (C 1 -C 4 )-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R5e is methoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5e is hydroxyl.
  • the invention relates to any one of the aforementioned compounds, wherein R5e is –OCF 3 . In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5e is substituted (C 1 -C 4 )-alkylene-(C 1 -C 4 )-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R5e is unsubstituted (C 1 -C 4 )-alkylene-(C 1 -C 4 )-alkoxy. In certain embodiments, (C 1 -C 4 )- alkylene-(C 1 -C 4 )-alkoxy is –CH 2 OMe.
  • R 5b is H. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R5b is substituted or unsubstituted (C 1 -C 4 )- alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5b is unsubstituted (C 1 -C 4 )-alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R5b is substituted (C 1 -C 4 )-alkyl. In certain embodiments, the substituted (C 1 -C 5 )-alkyl, is substituted with one or more halogen. In certain embodiments, the halogen is Cl or F.
  • R 5b is methyl, ethyl, isopropyl, n-propyl, i-butyl, n-butyl, or t-butyl.
  • the invention relates to any one of the aforementioned compounds, wherein R5b is halide.
  • the halide is Cl or F.
  • R 5b is substituted (C 3 -C 6 )- cycloalkyl.
  • R 5b is unsubstituted (C 3 -C 6 )-cycloalkyl.
  • (C 3 -C 6 )-cycloalkyl is cyclopropyl.
  • the invention relates to any one of the aforementioned compounds, wherein R 5b is CF 3 . In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R5b is C(H)F 2 . In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R5b is C(F)H 2 . In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5a is (C 1 -C 4 )-alkoxy. In some embodiments, (C 1 -C 4 )-alkoxy is methoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R5b is methoxy.
  • the invention relates to any one of the aforementioned compounds, wherein R 5b is hydroxyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R5b is –OCF 3 . In certain embodiments, R5b is CN. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5b is substituted (C 1 -C 4 )- alkylene-(C 1 -C 4 )-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R5b is unsubstituted (C 1 -C 4 )-alkylene-(C 1 -C 4 )-alkoxy.
  • (C 1 -C 4 )-alkylene-(C 1 -C 4 )-alkoxy is –CH 2 OMe.
  • R 5b is CH 2 OH.
  • R5c is H.
  • the invention relates to any one of the aforementioned compounds, wherein R5c is substituted or unsubstituted (C 1 -C 4 )- alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5a is unsubstituted (C 1 -C 4 )-alkyl.
  • the invention relates to any one of the aforementioned compounds, wherein R5c is substituted (C 1 -C 4 )-alkyl. In certain embodiments, the substituted (C 1 -C 5 )-alkyl, is substituted with one or more halogen. In certain embodiments, the halogen is Cl or F. In certain embodiments, R 5c is methyl, ethyl, isopropyl, n-propyl, i-butyl, n-butyl, or t-butyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R5c is halide. In some embodiments, the halide is Cl or F.
  • R 5c is substituted (C 3 -C 6 )- cycloalkyl. In certain embodiments, R5c is unsubstituted (C 3 -C 6 )-cycloalkyl. In some embodiments, (C 3 -C 6 )-cycloalkyl is cyclopropyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5c is CF 3 . In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R5c is C(H)F 2 . In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5c is C(F)H 2 .
  • the invention relates to any one of the aforementioned compounds, wherein R 5c is (C 1 -C 4 )-alkoxy. In some embodiments, (C 1 -C 4 )-alkoxy is methoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5c is methoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5c is hydroxyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R5c is –OCF 3 . In certain embodiments, R5c is CN.
  • the invention relates to any one of the aforementioned compounds, wherein R 5a is substituted (C 1 -C 4 )- alkylene-(C 1 -C 4 )-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R5c is unsubstituted (C 1 -C 4 )-alkylene-(C 1 -C 4 )-alkoxy. In certain embodiments, (C 1 -C 4 )-alkylene-(C 1 -C 4 )-alkoxy is –CH 2 OMe. In certain embodiments, R 5c is CH 2 OH. In certain embodiments, R 5d is H.
  • the invention relates to any one of the aforementioned compounds, wherein R 5d is substituted or unsubstituted (C 1 -C 4 )- alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5d is unsubstituted (C 1 -C 4 )-alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5d is substituted (C 1 -C 4 )-alkyl. In certain embodiments, the substituted (C 1 -C 5 )-alkyl, is substituted with one or more halogen. In certain embodiments, the halogen is Cl or F.
  • R 5d is methyl, ethyl, isopropyl, n-propyl, i-butyl, n-butyl, or t-butyl.
  • the invention relates to any one of the aforementioned compounds, wherein R 5d is halide.
  • the halide is Cl or F.
  • R 5d is substituted (C 3 -C 6 )- cycloalkyl.
  • R 5d is unsubstituted (C 3 -C 6 )-cycloalkyl.
  • (C 3 -C 6 )-cycloalkyl is cyclopropyl.
  • the invention relates to any one of the aforementioned compounds, wherein R 5d is CF 3 . In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5d is C(H)F 2 . In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5d is C(F)H 2 . In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5d is (C 1 -C 4 )-alkoxy. In some embodiments, (C 1 -C 4 )-alkoxy is methoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5d is methoxy.
  • the invention relates to any one of the aforementioned compounds, wherein R 5d is hydroxyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5d is –OCF 3. In certain embodiments, R 5d is CN. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5d is substituted (C 1 -C 4 )- alkylene-(C 1 -C 4 )-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5d is unsubstituted (C 1 -C 4 )-alkylene-(C 1 -C 4 )-alkoxy.
  • (C 1 -C 4 )-alkylene-(C 1 -C 4 )-alkoxy is –CH 2 OMe.
  • R 5d is CH 2 OH.
  • R5e is H.
  • the invention relates to any one of the aforementioned compounds, wherein R 5e is substituted or unsubstituted (C 1 -C 4 )- alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R5e is unsubstituted (C 1 -C 4 )-alkyl.
  • the invention relates to any one of the aforementioned compounds, wherein R 5e is substituted (C 1 -C 4 )-alkyl. In certain embodiments, the substituted (C 1 -C 5 )-alkyl, is substituted with one or more halogen. In certain embodiments, the halogen is Cl or F. In certain embodiments, R5e is methyl, ethyl, isopropyl, n-propyl, i-butyl, n-butyl, or t-butyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5e is halide. In some embodiments, the halide is Cl or F.
  • R5e is substituted (C 3 -C 6 )- cycloalkyl. In certain embodiments, R5e is unsubstituted (C 3 -C 6 )-cycloalkyl. In some embodiments, (C 3 -C 6 )-cycloalkyl is cyclopropyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R5e is CF 3 . In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5e is C(H)F 2 . In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5e is C(F)H 2 .
  • the invention relates to any one of the aforementioned compounds, wherein R5e is (C 1 -C 4 )-alkoxy. In some embodiments, (C 1 -C 4 )-alkoxy is methoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5e is methoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R5e is hydroxyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5e is –OCF 3. In certain embodiments, R 5e is CN.
  • the invention relates to any one of the aforementioned compounds, wherein R5e is substituted (C 1 -C 4 )- alkylene-(C 1 -C 4 )-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R 5e is unsubstituted (C 1 -C 4 )-alkylene-(C 1 -C 4 )-alkoxy. In certain embodiments, (C 1 -C 4 )-alkylene-(C 1 -C 4 )-alkoxy is –CH 2 OMe. In certain embodiments, R5e is CH 2 OH. In some embodiments, R 5a and R 5e are identical.
  • R 5a and R 5e can both be substituted or unsubstituted (C 1 -C 4 )-alkyl.
  • R 5a and R 5e are both unsubstituted (C 1 -C 4 )-alkyl (e.g., methyl).
  • R5a and R5e are both unsubstituted methyl.
  • R 5b and R 5d are identical.
  • R 5a and R 5e can both be hydrogen.
  • R5a and R5e are both substituted, and R5b and R 5d are both hydrogen.
  • R 5a and R 5e can both be (the same or different) substituted or unsubstituted (C 1 -C 4 )-alkyl.
  • R5a and R5e can both be unsubstituted (C1- C4)-alkyl (e.g., methyl) and R5b and R 5d are both hydrogen.
  • R5a and R5e are both unsubstituted methyl and R 5b and R 5d are both hydrogen.
  • R 5a , and R5e are independently selected from the group consisting of H, CN, halide, CF 3 , C(H)F 2 , C(F)H 2 , (C 1 -C 5 )-alkyl, hydroxyl, and (C 1 -C 4 )-alkoxy.
  • R 5c is hydrogen, halide (e.g., F), substituted or unsubstituted (C 1 -C 4 )-alkoxy (e.g., methoxy), or substituted or unsubstituted (C 1 -C 4 )-alkyl (e.g., methyl).
  • R5a and R5e are both substituted or unsubstituted (C 1 -C 5 )-alkyl
  • both R 5b and R 5d are hydrogen
  • R 5c is hydrogen, halide (e.g., F), substituted or unsubstituted (C 1 -C 4 )-alkoxy (e.g., methoxy), or substituted or unsubstituted (C 1 -C 4 )-alkyl (e.g., methyl).
  • R5a and R5e can both be methyl; R5b and R 5d are both hydrogen; and R 5c is selected from the group consisting of hydrogen, halide (e.g., F), substituted or unsubstituted (C 1 -C 4 )-alkoxy (e.g., methoxy), and substituted or unsubstituted (C 1 -C 4 )-alkyl (e.g., methyl).
  • R5a and R5e can both be methyl; R5b and R 5d are both hydrogen; and R 5c is selected from the group consisting of hydrogen, F, Cl, methoxy, and methyl.
  • R 5a , R 5c and R 5e are each methyl; and R 5b and R 5d are both hydrogen.
  • R5b, R5c, and R 5d are independently selected from the group consisting of H, CN, halide, CF 3 , C(H)F 2 , C(F)H 2 , (C 1 -C 5 )-alkyl, hydroxyl, and (C 1 -C 4 )- alkoxy.
  • the invention relates to any one of the aforementioned compounds, wherein R a , R b and R c comprise a charged amine.
  • At least one of R a , R b and R c can be a substituted or unsubstituted –(C 1 -C 5 )alkylene-N-(R x )(R y ); wherein R x and R y are independently selected from the group consisting of H, substituted or unsubstituted (C 1 -C 6 )- alkyl, or substituted or unsubstituted (C 1 -C 4 )-alkylene-(C 1 -C 4 )-alkoxy; or R x and R y taken together with the N to which they are attached form a substituted or unsubstituted 4-6 membered heterocyclyl ring.
  • the invention relates to any one of the aforementioned compounds, wherein only one of R a , R b and R c is a substituted or unsubstituted –(C 1 - C 5 )alkylene-N-(R x )(R y ); wherein R x and R y are independently selected from the group consisting of H, substituted or unsubstituted (C 1 -C 6 )-alkyl, or substituted or unsubstituted (C 1 -C 4 )-alkylene-(C 1 -C 4 )-alkoxy.
  • the invention relates to any one of the aforementioned compounds, wherein only one of R a , R b and R c is a substituted or unsubstituted –(C 1 -C 5 )alkylene-N-(R x )(R y ); wherein R x and R y are independently selected from the group consisting of substituted or unsubstituted (C 1 -C 6 )-alkyl, or substituted or unsubstituted (C 1 -C 4 )-alkylene-(C 1 -C 4 )-alkoxy.
  • the invention relates to any one of the aforementioned compounds, wherein only one of R a , R b and R c is a substituted or unsubstituted –(C 1 -C 5 )alkylene-N-(R x )(R y ); wherein R x and R y are independently selected from the group consisting of substituted or unsubstituted (C 1 -C 6 )- alkyl.
  • the invention relates to any one of the aforementioned compounds, wherein only one of R a , R b and R c is a substituted or unsubstituted –(C1- C5)alkylene-N-(R x )(R y ); wherein R x and R y taken together with the N to which they are attached form a substituted or unsubstituted 4-6 membered heterocyclyl ring.
  • the invention relates to any one of the aforementioned compounds, wherein only one of R a , R b and R c is a substituted or unsubstituted –(C 1 -C 5 )alkylene-N-(R x )(R y ); wherein R x and R y taken together with the N to which they are attached form a 4-6 membered heterocyclyl ring optionally substituted with one or more halide (e.g., F, Cl).
  • halide e.g., F, Cl
  • R a , R b , and R c are independently selected from the group consisting of H, substituted or unsubstituted (C 1 -C 5 )-alkyl, halide, CF 3 , C(H)F 2 , C(F)H 2 , substituted or unsubstituted (C 1 -C 4 )-alkoxy, -OCF 3 , and at least one of R a , R b , and R c is --– (C1-C3)alkylene-N-(R x )(R y ) wherein R x and R y are independently selected from the group consisting of H and (C 1 -C 6 )-alkyl; or R x and R y taken together with the N to which they are attached form a 4-6 membered heterocyclyl ring optionally substituted with one or more halide (e.g., F, or Cl).
  • halide e.g., F, or Cl
  • R a , R b , and R c are independently selected from the group consisting of H, substituted or unsubstituted (C 1 -C 5 )-alkyl, halide, CF 3 , C(H)F 2 , C(F)H 2 , substituted or unsubstituted (C 1 -C 4 )-alkoxy, -OCF 3 , and at least one of R a , R b , and R c is –(C 1 - C3)alkylene-N-(R x )(R y ) wherein R x and R y are independently selected from the group consisting of (C 1 -C 6 )-alkyl (e.g., methyl); or R x and R y taken together with the N to which they are attached form a 4-6 membered heterocyclyl ring optionally substituted with one or more halide (e.g., F, or Cl).
  • halide e.g.
  • the invention relates to any one of the aforementioned compounds, wherein only one of R a , R b and R c is selected from the group consisting of some embodiments, R a is In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R a is selected from the group consisting of H, substituted or unsubstituted (C 1 -C 5 )-alkyl, halide, CF 3 , C(H)F 2 , C(F)H 2 , substituted or unsubstituted (C 1 - C4)-alkoxy, and -OCF 3 .
  • the invention relates to any one of the aforementioned compounds, wherein R a is selected from the group consisting of H, substituted or unsubstituted (C 1 -C 5 )-alkyl, halide, CF 3 , C(H)F 2 , C(F)H 2 , substituted or unsubstituted (C 1 -C 4 )-alkoxy, and -OCF 3 ; and one of R b and R c is a substituted or unsubstituted –(C 1 -C 5 )alkylene-N-(R x )(R y ); wherein R x and R y are independently selected from the group consisting of H, substituted or unsubstituted (C 1 -C 6 )-alkyl, or substituted or unsubstituted (C 1 -C 4 )-alkylene-(C 1 -C 4 )-alkoxy; or R x and R y taken together
  • the invention relates to any one of the aforementioned compounds, wherein R a is H. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R a is Me. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R a is halide. In some embodiments, halide is Cl or F. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R a is CF 3 . In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R a is C(H)F 2 . In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R a is C(F)H 2 .
  • the invention relates to any one of the aforementioned compounds, wherein R a is substituted (C 1 -C 4 )-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R a is unsubstituted (C 1 -C 4 )-alkoxy. In some embodiments, (C 1 -C 4 )-alkoxy is methoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R a is -OCF 3 .
  • the invention relates to any one of the aforementioned compounds, wherein R a is substituted –(C 1 - C 5 )alkylene-N-(R x )(R y ). In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R a is unsubstituted –(C 1 -C 5 )alkylene-N-(R x )(R y ). In some embodiments, –(C 1 -C 5 )alkylene of –(C 1 -C 5 )alkylene-N-(R x )(R y ) is substituted with one or more halide or –(C 1 -C 4 )alkyl.
  • the invention relates to any one of the aforementioned compounds, wherein ––(C 1 -C 5 )alkylene-N-(R x )(R y ) is ––(C 1 -C 4 )alkylene- N-(R x )(R y ).
  • R a is substituted (C 1 -C 5 )-alkyl, substituted (C 1 -C 4 )-alkoxy, or substituted –(C 1 -C 5 )alkylene-N-(R x )(R y ), wherein substituted means substituted with halide or (C 1 -C 4 )-alkoxy.
  • R a is substituted (C 1 -C 5 )-alkyl, substituted (C 1 -C 4 )- alkoxy, or substituted –(C 1 -C 5 )alkylene-N-(R x )(R y ), wherein substituted means substituted with F or methoxy.
  • R a is selected from the group consisting of , In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R a is selected from the group consisting of H, substituted or unsubstituted (C 1 -C 5 )-alkyl, halide, CF 3 , C(H)F 2 , C(F)H 2 , substituted or unsubstituted (C 1 -C 4 )-alkoxy, and - OCF; and R b is a substituted or unsubstituted –(C 1 -C 5 )alkylene-N-(R x )(R y ); wherein R x and R y are independently selected from the group consisting of H, substituted or unsubstituted (C 1 - C 6 )-alkyl, or substituted or unsubstituted (C 1 -C 4 )-alkylene-(C 1 -C 4 )-alkoxy;
  • the invention relates to any one of the aforementioned compounds, wherein R b is H. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R b is Me. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R b is halide. In some embodiments, halide is Cl or F. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R b is CF 3 . In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R b is C(H)F 2 . In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R b is C(F)H 2 .
  • the invention relates to any one of the aforementioned compounds, wherein R b is substituted (C 1 -C 4 )-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R b is unsubstituted (C 1 -C 4 )-alkoxy. In some embodiments, (C 1 -C 4 )-alkoxy is methoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R b is -OCF 3 .
  • the invention relates to any one of the aforementioned compounds, wherein R b is substituted –(C1- C5)alkylene-N-(R x )(R y ). In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R b is unsubstituted –(C 1 -C 5 )alkylene-N-(R x )(R y ). In some embodiments, –(C 1 -C 5 )alkylene of –(C 1 -C 5 )alkylene-N-(R x )(R y ) is substituted with one or more halide or –(C 1 -C 4 )alkyl.
  • the invention relates to any one of the aforementioned compounds, wherein ––(C 1 -C 5 )alkylene-N-(R x )(R y ) is ––(C 1 -C 4 )alkylene- N-(R x )(R y ).
  • R b is substituted (C 1 -C 5 )-alkyl, substituted (C 1 -C 4 )-alkoxy, or substituted –(C 1 -C 5 )alkylene-N-(R x )(R y ), wherein substituted means substituted with halide or (C 1 -C 4 )-alkoxy.
  • R b is substituted (C 1 -C 5 )-alkyl, substituted (C 1 -C 4 )- alkoxy, or substituted –(C 1 -C 5 )alkylene-N-(R x )(R y ), wherein substituted means substituted with F or methoxy.
  • R b is selected from the group consisting of ,
  • the invention relates to any one of the aforementioned compounds, wherein R c is H.
  • the invention relates to any one of the aforementioned compounds, wherein R c is Me.
  • the invention relates to any one of the aforementioned compounds, wherein R c is halide.
  • halide is Cl or F.
  • the invention relates to any one of the aforementioned compounds, wherein R c is CF 3 .
  • the invention relates to any one of the aforementioned compounds, wherein R c is C(H)F 2 .
  • the invention relates to any one of the aforementioned compounds, wherein R c is C(F)H 2 .
  • the invention relates to any one of the aforementioned compounds, wherein R c is substituted (C 1 -C 4 )-alkoxy. In some embodiments, (C 1 -C 4 )-alkoxy is methoxy.
  • the invention relates to any one of the aforementioned compounds, wherein R c is unsubstituted (C 1 -C 4 )-alkoxy. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R c is -OCF 3 . In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R c is substituted –(C 1 - C5)alkylene-N-(R x )(R y ). In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R c is unsubstituted –(C 1 -C 5 )alkylene-N-(R x )(R y ).
  • –(C 1 -C 5 )alkylene of –(C 1 -C 5 )alkylene-N-(R x )(R y ) is substituted with one or more halide or –(C 1 -C 4 )alkyl.
  • the invention relates to any one of the aforementioned compounds, wherein ––(C 1 -C 5 )alkylene-N-(R x )(R y ) is ––(C 1 -C 4 )alkylene- N-(R x )(R y ).
  • R c is substituted (C 1 -C 5 )-alkyl, substituted (C 1 -C 4 )-alkoxy, or substituted –(C 1 -C 5 )alkylene-N-(R x )(R y ), wherein substituted means substituted with halide or (C 1 -C 4 )-alkoxy.
  • R c is substituted (C 1 -C 5 )-alkyl, substituted (C 1 -C 4 )- alkoxy, or substituted –(C 1 -C 5 )alkylene-N-(R x )(R y ), wherein substituted means substituted with F or methoxy.
  • R c is selected from the group consisting of , In some embodiments, at least one of R a , R b , and R c is H. In some embodiments, at least one of R a , R b , and R c is a charged amine; and at least one of R a , R b , and R c is H. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R x is H. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R x is substituted (C 1 -C 6 )-alkyl.
  • the invention relates to any one of the aforementioned compounds, wherein R x is unsubstituted (C 1 -C 6 )-alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R x is substituted (C 1 -C 4 )-alkyl. In some embodiments (C 1 -C 6 )-alkyl is substituted with OMe, CN, or halide. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R x is unsubstituted (C 1 -C 4 )-alkyl.
  • the invention relates to any one of the aforementioned compounds, wherein R x is (C 1 -C 4 )-alkylene-(C 1 -C 4 )-alkoxy. In some embodiments, (C 1 -C 4 )-alkylene-(C 1 -C 4 )-alkoxy is –(CH 2 ) 2 OMe. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R x is Me. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R y is H.
  • the invention relates to any one of the aforementioned compounds, wherein R y is substituted (C 1 -C 6 )-alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R y is unsubstituted (C 1 -C 6 )-alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R y is substituted (C 1 -C 4 )-alkyl. In some embodiments (C 1 -C 6 )-alkyl is substituted with OMe, CN, or halide.
  • the invention relates to any one of the aforementioned compounds, wherein R y is unsubstituted (C 1 -C 4 )-alkyl. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R y is (C 1 -C 4 )-alkylene-(C 1 -C 4 )-alkoxy. In some embodiments, (C 1 -C 4 )-alkylene-(C 1 -C 4 )-alkoxy is –(CH 2 )2OMe. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R y is Me.
  • the invention relates to any one of the aforementioned compounds, wherein R x is Me; and R y is Me. In certain embodiments, the invention relates to any one of the aforementioned compounds, wherein R x and R y taken together with the N to which they are attached form a substituted or unsubstituted 4-6 membered ring.
  • the 4-6 membered ring is a substituted or unsubstituted heterocycloalkyl.
  • the substituted 4-6 membered heterocyclalkyl is substituted with halide of (C 1 -C 6 )alkyl.
  • the 4-6 membered ring is a substituted or unsubstituted heteroaryl.
  • the substituted 4-6 membered heteroaryl is substituted with halide of (C 1 -C 6 )alkyl.
  • the 4-6 membered ring is selected from .
  • the invention relates to a compound of Formula (Ia) or (Ib):
  • R 1 , R 3c , R 3d , R 5a , R 5b , R 5c , R 5d , R 5e , R a , R b , and R c are as defined above with respect to Formula (I);
  • R 4 is H; and at least one of R a , R b , and R c is –(C 1 -C 3 )alkylene-N(R x )(R y );
  • R x and R y are independently selected from the group consisting of H and methyl; or R x and R y taken together with the N to which they are attached form a 4-6 membered ring; and
  • R3a, and R3b are each independently selected from the group consisting of methyl and F.
  • the invention relates to any of the compounds depicted in Figure 1.
  • the invention relates to a compound selected from the group consisting of: (3S)-3-(4,5-difluoro-2',6'-dimethylbiphenyl-3-yl)-3-(2-(5-(2-(3-fluoroazetidin-1- yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid; (3S)-3-(2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4- methylpentanamido)-3-(4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoic acid; (3S)-3-(2-(2-(2-(4,5-d
  • the invention relates to a compound selected from the group consisting of: (S)-3-(4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(5-(2-(3- fluoroazetidin-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid; (S)-3-((S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4- methylpentanamido)-3-(4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3- yl)propynoic acid; (S)-3-((S)-2
  • the invention relates to any one of the aforementioned compounds, wherein the compound is in the form of a pharmaceutically acceptable salt.
  • a compound of Formula (I) (including compounds of Formula (Ia) and Formula (Ib) as provided herein), as well as pharmaceutically acceptable salts thereof, may be the active pharmaceutical ingredient (API) combined with one or more other ingredients to form a drug substance pharmaceutical composition.
  • the drug substance (DS) pharmaceutical composition can comprise the API (i.e., a compound of Formula (I) or pharmaceutically acceptable salt thereof) and one or more pharmaceutically acceptable carriers, diluents, and/or excipients.
  • the carrier(s), diluent(s) or excipient(s) can be selected to be compatible with the other ingredients of the formulation and appropriately safe and effective for an intended therapy.
  • a desired weight concentration of the compound of Formula (I) as the active pharmaceutical ingredient (API) can be combined with the other inactive ingredients to form a drug substance (DS) in a formulation batch.
  • Pharmaceutically acceptable compositions can be formulated for administration by an appropriate route, for example by the oral delivery (including as a capsule or tablet) in unit dosage forms. Such compositions may be prepared by bringing into association the active pharmaceutical ingredient (API) comprising a compound of Formula (I) with the carrier(s) or excipient(s).
  • the invention provides a pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API). In certain embodiments, the invention provides a pharmaceutical composition comprising the compound of Formula (Ia), or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API). In certain embodiments, the invention provides a pharmaceutical composition comprising the compound of Formula (Ib), or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound (3S)-3-(4,5-difluoro-2',6'-dimethylbiphenyl-3-yl)-3-(2-(5-(2-(3- fluoroazetidin-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)propanoic acid or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).
  • API active pharmaceutical ingredient
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound (3S)-3-(2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',6'-dimethyl-5- (trifluoromethyl)biphenyl-3-yl)propanoic acid or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).
  • API active pharmaceutical ingredient
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound (3S)-3-(2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(3',4-difluoro-2',5,6'-trimethyl- [1,1'-biphenyl]-3-yl)propanoic acid or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).
  • API active pharmaceutical ingredient
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound (3S)-3-(2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-3'-methoxy-2',5,6'- trimethyl-[1,1'-biphenyl]-3-yl)propanoic acid or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).
  • API active pharmaceutical ingredient
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound (3S)-3-(4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-(2- (5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4- methylpentanamido)propanoic acid or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).
  • API active pharmaceutical ingredient
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound (3S)-3-(5-chloro-4-fluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3- (2-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4- methylpentanamido)propanoic acid or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).
  • API active pharmaceutical ingredient
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'- tetramethylbiphenyl-3-yl)propanoic acid or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).
  • API active pharmaceutical ingredient
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound (3S)-3-(4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-(2- (3-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4- methylpentanamido)propanoic acid or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).
  • API active pharmaceutical ingredient
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin- 1(2H)-yl)-5-methylhexanamido)-3-(4-fluoro-2',5,6'-trimethylbiphenyl-3-yl)propanoic acid or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).
  • API active pharmaceutical ingredient
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound (3S)-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(3- fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4- methylpentanamido)propanoic acid or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).
  • API active pharmaceutical ingredient
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound (3S)-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(3- fluoro-5-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4- methylpentanamido)propanoic acid or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).
  • API active pharmaceutical ingredient
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound (S)-3-(4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2- (5-(2-(3-fluoroazetidin-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4- methylpentanamido)propanoic acid or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).
  • API active pharmaceutical ingredient
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound (S)-3-((S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',6'-dimethyl-5- (trifluoromethyl)-[1,1'-biphenyl]-3-yl)propanoic acid or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).
  • API active pharmaceutical ingredient
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound (S)-3-((S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(3',4-difluoro-2',5,6'-trimethyl- [1,1'-biphenyl]-3-yl)propanoic acid or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).
  • API active pharmaceutical ingredient
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound (S)-3-((S)-2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-3'-methoxy-2',5,6'- trimethyl-[1,1'-biphenyl]-3-yl)propanoic acid or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).
  • API active pharmaceutical ingredient
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound (S)-3-(4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2- (5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4- methylpentanamido)propanoic acid or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).
  • API active pharmaceutical ingredient
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound (S)-3-(5-chloro-4-fluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3- ((S)-2-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4- methylpentanamido)propanoic acid or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).
  • API active pharmaceutical ingredient
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl- [1,1'-biphenyl]-3-yl)propanoic acid or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).
  • API active pharmaceutical ingredient
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound (S)-3-(4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2- (3-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4- methylpentanamido)propanoic acid or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).
  • API active pharmaceutical ingredient
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound (S)-3-((S)-2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin- 1(2H)-yl)-5-methylhexanamido)-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoic acid or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).
  • API active pharmaceutical ingredient
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound (S)-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(3- fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4- methylpentanamido)propanoic acid or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).
  • API active pharmaceutical ingredient
  • the invention provides a pharmaceutical composition comprising the compound (S)-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(3- fluoro-5-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4- methylpentanamido)propanoic acid or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).
  • the invention relates to a pharmaceutical composition comprising a compound selected from the group consisting of: and or a pharmaceutically acceptable salt thereof.
  • compositions comprising the compound of Formula (I) can be prepared by various procedures.
  • the compounds of Formula (I) can be formulated with suitable excipients, diluents, or carriers, and formed into tablets, or capsules, and other suitable dosage forms.
  • Pharmaceutical compositions can be provided in unit dose forms containing a predetermined amount of API comprising a compound of Formula (I) per unit dose.
  • Such a unit may contain, a desired amount of a compound of the Formula (I) or pharmaceutically acceptable salt thereof, depending on the condition being treated, the route of administration and the age, weight and condition of the patient.
  • Such unit doses may therefore be administered at a desired dose interval.
  • the concentration of active compound in the drug composition will depend on various applicable parameters and considerations such as the absorption, inactivation and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.
  • the active ingredient can be administered at once, or can be divided into a number of smaller doses to be administered at varying intervals of time.
  • the mode of administration of the active compound is oral.
  • Oral compositions will generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets.
  • the active compound can be incorporated with excipients and used in the form of tablets, troches or capsules.
  • Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • Pharmaceutical compositions comprising a compound of Formula (I) formulated for oral delivery can be prepared in a unit dosage form, such as a capsule at a desired dosage strength of the compound of Formula (I).
  • the oral drug components can be combined with any oral, non- toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • the compound of Formula (I) can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier.
  • excipients, diluents, and carriers that are suitable for such formulations include the following: fillers and extenders such as starch, and sugars; and binding agents such as cellulose derivatives.
  • suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture.
  • Suitable binders include starch, natural sugars, natural and synthetic gums, and the like.
  • Lubricants and/or glidants can be used in these dosage forms.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel or
  • the dosage unit form When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil.
  • unit dosage forms can contain various other materials that modify the physical form of the dosage unit, for example, coatings of sugar, or other enteric agents.
  • the compound can be administered as a component of an elixir, suspension, syrup, wafer, or the like.
  • a syrup can contain, in addition to the active compound(s), sucrose or sweetener as a sweetening agent and certain preservatives, dyes and colorings and flavors.
  • the compounds can be formulated as solutions appropriate for parenteral administration, for example, by intramuscular, subcutaneous or intravenous routes.
  • a compound of Formula (I) can be dissolved in a suitable buffer.
  • a pharmaceutical composition comprising a desired concentration of a compound of Formula (I) can be formulated as an injectable drug solution in (useful, e.g., in preclinical animal studies).
  • EXEMPLARY METHODS Compounds inhibiting ⁇ 4 ⁇ 7 are useful for development of medicaments to treat ulcerative colitis and Crohn’s disease patients. Ulcerative colitis (UC) and Crohn’s disease (CD) patients suffer from autoimmune inflammation in the digestive tract and for many of these patients, the CD4 + memory T cells drive the progression and flare ups of the disease via their ability to secrete pro-inflammatory, effector cytokines within the gut, impacting the surrounding immune cells and tissue.
  • T cell homing to the gut requires surface expression of integrin ⁇ 4 ⁇ 7 and chemokine receptor CCR9. While CCR9 is utilized by the cell to migrate against the gradient of CCL25 expressed in the small intestine, ⁇ 4 ⁇ 7 is a tethering molecule which binds the ligand, mucosal addressin cell adhesion molecule 1 (MAdCAM-1).
  • MAdCAM-1 mucosal addressin cell adhesion molecule 1
  • Integrin ⁇ 4 ⁇ 7 binds MAdCAM-1 with high affinity facilitating rolling and firm adhesion of cells followed by extravasation into tissue.
  • Pharmaceutical compositions can comprise compounds that inhibit the ⁇ 4 ⁇ 7 integrin on inflammatory cells that enables adhesion of these cells to mucosal addressin cell adhesion molecule-1 (MAdCAM-1), and inhibiting or preventing these cells from entering the gut lamina intestinal and gut associated lymphoid tissue.
  • Compounds of Formula (I) were evaluated using a fluorescent polarization (FP) assay. FP assays are used to evaluate potency of compounds on purified protein.
  • the FP assays consists of measuring purified integrin ⁇ heterodimer ecto domains or headpiece binding to surrogate or truncated ligands. Results of the FP assay for exemplary compounds of Formula (I) are provided herein. Compounds of Formula (I) were further evaluated using a Ligand binding assay (LBA) to examine compound potency of free ligand binding to receptors expressed on cells.
  • LBA Ligand binding assay
  • the MAdCAM ligand binding assay uses flow cytometry to measure the binding of fluorescently- labeled MAdCAM-1-Fc to RPMI 8866 cells in the presence of Mn++. This assay assesses the binding of compounds to native full-length receptors on the cell surface.
  • MAdCAM ligand binding assay is its ability to quantify and discriminate the activity of potent compounds that exceed the FP assay’s functional sensitivity limit [ ⁇ 10nM in Mn].
  • Ligand binding assays are used to examine compound potency and selectivity of free ligand binding to receptors expressed on cells.
  • compounds of the invention can be selected from one or more of the following numbered embodiments: 1.
  • R a , R b , and R c are independently selected from the group consisting of H, Me, halide, CF 3 , C(H)F 2 , C(F)H 2 , and –(C 1- C 5 )alkylene-N-(R x )(R y ); provided that at least one of R a , R b , and R c is -(C 1- C 5 )alkylene-N-(R x )(R y ); R x and R y are independently selected from the group consisting of H and substituted or unsubstituted (C 1 -C 6 )-alkyl; or R x and R y taken together with the N to which they are attached form a 4-6 membered ring; R 1 is substituted or unsubstituted (C 1 -C 6 )-alkyl, substituted or unsubstituted (C 1 -C 4 )- alkylene-(C 3 -C
  • R3a and R3b are independently selected from the group consisting of halide, substituted or unsubstituted (C 1 -C 5 )-alkyl, substituted or unsubstituted (C 3 -C 6 )-cycloalkyl, substituted or unsubstituted (C 1 -C 4 )-alkoxy, CF 3 , C(H)F 2 , and C(F)H 2 .
  • R 3a and R 3b are independently selected from the group consisting of halide and (C 1 -C 4 )-alkyl.
  • halide is Cl or F.
  • R5a and R5e are independently selected from the group consisting of halide, CF 3 , C(H)F 2 , C(F)H 2 , and substituted or unsubstituted (C 1 -C 4 )-alkyl.
  • R5a is halide.
  • R5a is F or Cl.
  • R 5a is CF 3 .
  • R 5a is C(H)F 2 .
  • R5a is C(F)H 2 .
  • R 5e is unsubstituted (C 1 - C4)-alkoxy.
  • 34 The compound of embodiment 33, wherein R5e is OMe.
  • 35 The compound of any one of embodiments 1-34, wherein R 5b , R 5c , and R 5d are independently selected from the group consisting of H, halide, CF 3 , C(H)F 2 , C(F)H 2 , substituted or unsubstituted (C 1 -C 5 )-alkyl, and substituted or unsubstituted (C 1 -C 4 )-alkoxy.
  • 36 The compound of any one of embodiments 1-35, wherein R 5b is H. 37.
  • R5b is halide. 38. The compound of embodiment 37, wherein R5b is Cl or F. 39. The compound of any one of embodiments 1-35, wherein R 5b is CF 3 . 40. The compound of any one of embodiments 1-35, wherein R5b is C(H)F 2 . 41. The compound of any one of embodiments 1-35, wherein R5b is C(F)H 2 . 42. The compound of any one of embodiments 1-35, wherein R 5b is unsubstituted (C 1 - C4)-alkyl. 43. The compound of embodiment 37, wherein R5b is methyl. 44.
  • the compound of embodiment 108, wherein R 5a , and R 5e are independently unsubstituted (C 1 -C 4 ) alkyl.
  • R a is selected from the group consisting of H, C(H)F 2 , CF 3 , and Me. 112.
  • the compound of embodiment 1 or 108, wherein R b is selected from the group 113.
  • the compound of embodiment 1 or 108, wherein R b is selected from the group consisting 114.
  • the compound of any one of embodiments 1, and 108-121, wherein R5b, R5c, and R 5d are H. 152.
  • the compound of any one of embodiments 1, and 108-151, wherein R3a is H. 153.
  • R a , R b , and R c are independently selected from the group consisting of H, substituted or unsubstituted (C 1 -C 5 )-alkyl, halide, CF 3 , C(H)F 2 , C(F)H 2 , substituted or unsubstituted (C1- C 4 )-alkoxy, -OCF 3 , and substituted or unsubstituted –(C 1 -C 5 )alkylene-N-(R x )(R y ); provided that one of R a , R b , and R c is –(C 1 -C 5 )alkylene-N-(R x )(R y ); R x and R y are independently selected from the group consisting of H, substituted or unsubstituted (C 1 -C 6 )
  • a method of inhibiting ⁇ 4 ⁇ 7 integrin in a cell comprising contacting the cell with a compound of any one of embodiments 1-208 under conditions effective to reduce the adhesion of the cell to MAdCAM-1.
  • a method of reducing the adhesion of a cell comprising an ⁇ 4 ⁇ 7 integrin to MAdCAM-1 the method comprising contacting the cell with a compound of any one of embodiments 1-208 under conditions effective to reduce the adhesion of the cell to MAdCAM-1.
  • compounds of the invention can be a compound of Formula (I): wherein R a , R b , and R c are independently selected from the group consisting of H, Me, halide, CF 3 , C(H)F 2 , C(F)H 2 , and –(C 1 -C 5 )alkylene-N-(R x )(R y ); provided that at least one of R a , R b , and R c is -(C 1- C 5 )alkylene-N-(R x )(R y ); R x and R y are independently selected from the group consisting of H and substituted or unsubstituted (C 1 -C 6 )-alkyl; or R x and R y taken together with
  • compounds of the invention can be a compound of Formula (Ia): wherein R a , R b , and R c are independently selected from the group consisting of H, Me, halide, CF 3 , C(H)F 2 , C(F)H 2 , and –(C 1 -C 5 )alkylene-N-(R x )(R y ); provided that at least one of R a , R b , and R c is -(C 1- C 5 )alkylene-N-(R x )(R y ); at least one of R a , R b , and R c is –(C1-C3)alkylene-N(R x )(R y ); R x and R y are independently selected from the group consisting of H and methyl; or R x and R y taken together with the N to which they are attached form a substituted or unsubstituted 4-6 membered ring
  • R a , R b , and R c are independently selected from the group consisting of H, substituted or unsubstituted (C 1 -C 5 )-alkyl, halide, CF 3 , C(H)F 2 , C(F)H 2 , substituted or unsubstituted (C 1 - C 4 )-alkoxy, -OCF 3 , and substituted or unsubstituted –(C 1 -C 5 )alkylene-N-(R x )(R y ); provided that one of R a , R b , and R c is –(C 1 -C 5 )alkylene-N-(R x )(R y ); R x and R y are independently selected from the group consisting of H, substituted or unsubstituted (C 1 -C 6 )-alkyl, or substituted or unsubstituted (C 1 -C 4 )-alkyl
  • compounds of the invention can be a compound (3S)-3-(2-(5-(2- (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3- (2-fluoro-3-methyl-5-((S)-2-methylpiperidin-1-yl)phenyl)propanoic acid
  • the invention relates to any one of the aforementioned methods, wherein the subject is a mammal. In certain embodiments, the invention relates to any one of the aforementioned methods, wherein the subject is human.
  • Compounds in Figure 1 can be prepared as a mixture of diastereomeric compounds (e.g., as disclosed in Examples 1-4) having a (3S) configuration (i.e., at the stereocenter beta to the carboxylic acid moiety), and a mixture of diastereomersat the chiral center covalently bound to the pyridone ring nitrogen atom of Formula (I) (e.g., as shown in Formula (Ib)).
  • compounds having greater activity in the fluorescence polarization (FP) assay of Example 5 are shown with the stereochemistry of Formula (Ia).
  • Example 5 describes a fluorescence polarization (FP) assay.
  • Example 6 describes a ligand binding (LB) assay.
  • Example 7 describes a cell adhesion (CA) assay. Additional Embodiments
  • a compound can be selected from one or more of the enumerated embodiments provided below: 1.
  • R3a and R3b are independently selected from the group consisting of halide, substituted or unsubstituted (C 1 -C 5 )-alkyl, substituted or unsubstituted (C 3 -C 6 )-cycloalkyl, substituted or unsubstituted (C 1 -C 4 )- alkoxy, CF 3 , C(H)F 2 , and C(F)H 2 .
  • R 3a and R 3b are independently selected from the group consisting of halide and (C 1 -C 4 )-alkyl.
  • halide is Cl or F.
  • R5a and R5e are independently selected from the group consisting of halide, CF 3 , C(H)F 2 , C(F)H 2 , and substituted or unsubstituted (C 1 -C 4 )-alkyl.
  • R5a is halide.
  • R 5a is F or Cl.
  • R 5a is CF 3 .
  • R5a is C(H)F 2 .
  • R5a is C(F)H 2 .
  • R 5b , R 5c , and R 5d are independently selected from the group consisting of H, halide, CF 3 , C(H)F 2 , C(F)H 2 , substituted or unsubstituted (C 1 -C 5 )-alkyl, and substituted or unsubstituted (C 1 -C 4 )- alkoxy.
  • R5b is H.
  • R5b is halide.
  • R5b, and R 5d are each H. 73.
  • R a , R b , and R c is –(C1-C3)alkylene-N(R x )(R y );
  • R x and R y are independently selected from the group consisting of H and methyl; or R x and R y taken together with the N to which they are attached form a substituted or unsubstituted 4-6 membered ring ; and
  • R3a, and R3b are each independently selected from the group consisting of methyl and F.
  • the compound of embodiment 108, wherein R5a, and R5e are independently unsubstituted (C 1 -C 4 ) alkyl. 110.
  • the compound of any one of embodiments 1, and 108-121, wherein at least one of R5b, R5c, and R 5d is H. 150.
  • the compound of any one of embodiments 1, and 108-121, wherein at least two of R 5b , R 5c , and R 5d is H. 151.
  • the compound of any one of embodiments 1, and 108-121, wherein R5b, R5c, and R 5d are H. 152.
  • the compound of any one of embodiments 1, and 108-151, wherein R 3a is H. 153.
  • the compound of any one of embodiments 1, and 108-151, wherein R3a is methyl.
  • the compound of any one of embodiments 1, and 108-151, wherein R3a is halide.
  • R a , R b , and R c are independently selected from the group consisting of H, substituted or unsubstituted (C 1 -C 5 )-alkyl, halide, CF 3 , C(H)F 2 , C(F)H 2 , substituted or unsubstituted (C 1 - C4)-alkoxy, -OCF 3 , and substituted or unsubstituted –(C 1 -C 5 )alkylene-N-(R x )(R y ); provided that one of R a , R b , and R c is –(C 1 -C 5 )alkylene-N-(R x )(R y ); R x and R y are independently selected from the group consisting of H, substituted or unsubstituted (C 1 -C 6 )-
  • the compound of embodiment 1, wherein the compound is the compound: or a pharmaceutically acceptable salt thereof. 181.
  • the compound of embodiment 1, wherein the compound is the compound: or a pharmaceutically acceptable salt thereof.
  • the compound of embodiment 1, wherein the compound is the compound: or a pharmaceutically acceptable salt thereof.
  • the compound of embodiment 1, wherein the compound is the compound: or a pharmaceutically acceptable salt thereof.
  • the compound of embodiment 1, wherein the compound is the compound: or a pharmaceutically acceptable salt thereof. 185.
  • a method of inhibiting ⁇ 4 ⁇ 7 integrin in a cell comprising contacting the cell with a compound of any one of embodiments 1-208 under conditions effective to reduce the adhesion of the cell to MAdCAM-1.
  • a method of reducing the adhesion of a cell comprising an ⁇ 4 ⁇ 7 integrin to MAdCAM-1 the method comprising contacting the cell with a compound of any one of embodiments 1-208 under conditions effective to reduce the adhesion of the cell to MAdCAM-1.
  • a method of treating inflammatory bowel disease, ulcerative colitis, or Crohn’s disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of embodiments 1-208.
  • Procedure B A mixture of aldehyde (1 equiv.), amine (1.05-2 equiv.) in DCE (3-4 mL/mmol of aldehyde) was stirred at room temperature for 10-30 mins. Then NaBH(OAc) 3 (3-4 equiv.) was added portion-wise and stirred at room temperature 1-16 until complete by LC/MS. The solvent was concentrated in vacuo and the residue was purified by silica gel chromatography to give the desired amine.
  • Procedure C A mixture of aldehyde (1 equiv.), AcOH (1.2 equiv), amine (1.05-2 equiv.) in DCM (2-3 mL/mmol aldehyde) and MeOH (0.5 mL/mmol aldehyde) was stirred at room temperature for 15-30 mins Then NaBH(OAc)3 (2 equiv.) was added portion-wise and stirred at room temperature 1-16 until complete by LC/MS. The solvent was concentrated in vacuo and the residue was purified by silica gel chromatography to give the desired amine.
  • Procedure B Enol ether (1 equiv.) was treated with HCOOH (2 mL/mmol) at 70°C for 2 hours. The solvent was removed in vacuo to provide the desired aldehyde.
  • Procedure C To a solution of enol ether (1 equiv.) in DCM (15 mL/mmol enol ether) was added TFA (2 mL/mmol) and water (0.25 mL/ mmol enol ether). The reaction was stirred at 45°C for 18 h. The reaction was worked up (quenched with NaHCO3, extracted with DCM; combined extracts dried over Na2SO4, filtered, and concentrated) to provide the desired aldehyde.
  • LC/MS A column: XBridge C18, 4.6 X 50 mm, 3.5 ⁇ m; mobile phase: A water (10 mM ammonium hydrogen carbonate), B CH 3 CN; gradient: 5%-95% B in 1.4 min, then 1.6 min hold; flow rate: 1.8 mL/min; oven temperature 50 °C.
  • LC/MS B column: SunFire C18, 4.6 X 50 mm, 3.5 ⁇ m; mobile phase: A water (0.01% TFA), B CH 3 CN; gradient: 5%-95% B in 1.5 min, then 1.5 min hold; flow rate: 2.0 mL/min; oven temperature 50 °C.
  • LC/MS C column: XBridge C18, 4.6 X 50 mm, 3.5 ⁇ m; mobile phase: A water (10 mM ammonium hydrogen carbonate), B CH3CN; gradient: 5%-95%B in 1.5min, then 1.5 min hold; flow rate: 1.8 mL/min; oven temperature 50 °C.
  • LC/MS D column: Poroshell 120 EC-C138, 4.6 X 30 mm, 2.7 ⁇ m; mobile phase: A water (0.01% TFA), B CH3CN (0.01% TFA); gradient: 5%-95% B in 1.2 min, then 1.8 min hold; flow rate: 2.2 mL/min; oven temperature 50 °C.
  • Example 2 Example 2.
  • Step 2 (R, E)-N-(5-bromo-2-fluoro-3-methylbenzylidene)-2-methylpropane-2- sulfinamide
  • 5-bromo-2-fluoro-3-methylbenzaldehyde 8.0 g, 36.9 mmol, 1.00 eq
  • (R)-2-methylpropane-2-sulfinamide 5.4 g, 44.3 mmol, 1.2 eq
  • Ti(OEt)4 (12.6 g, 55.4 mmol, 1.50 eq) dropwise at room temperature with the temperature maintained below 30 °C.
  • Step 3 ethyl (S)-3-(5-bromo-2-fluoro-3-methylphenyl)-3-(((R)-tert- butylsulfinyl)amino)propanoate ethyl 2-bromoacetate +
  • chlorotrimethylsilane 0.8 g, 7.5 mmol, 0.2 eq
  • Step 4 ethyl (S)-3-amino-3-(5-bromo-2-fluoro-3-methylphenyl)propanoate
  • ethyl (S)-3-(5-bromo-2-fluoro-3-methylphenyl)-3-(((R)-tert- butylsulfinyl)amino)propanoate 8.0 g, 19.6 mmol, 1.00 eq
  • DCM 20 mL
  • HCl-dioxane 4 M, 20 mL, 80.0 mmol, 4.08 eq
  • Step 5 ethyl (S)-ethyl 3-(5-bromo-2-fluoro-3-methylphenyl)-3-(tert- butoxycarbonylamino)propanoate
  • DCM 100 mL
  • DIEA 7.6 g, 59.0 mmol, 3.00 eq
  • Boc2O 8.6 g, 39.2 mmol, 2.00 eq
  • Step 2 ethyl (S)-3-amino-3-(2',4-difluoro-5,6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate
  • ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2',4-difluoro-5,6'- dimethyl-[1,1'-biphenyl]-3-yl)propanoate 210 mg, 0.48 mmol, 1.0 eq
  • DCM 2 mL
  • HCl-dioxane 4 M, 3.0 mL, 6.0 mmol, 12.5 eq
  • Step 2 ethyl (S)-3-amino-3-(2'-cyano-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3- yl)propanoate hydrochloride To a stirred solution of ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2'-cyano-4-fluoro-5,6'- dimethyl-[1,1'-biphenyl]-3-yl)propanoate (230 mg, 0.52 mmol, 1.0 eq) in DCM (2 mL) was added HCl-dioxane (4 M, 2.0 mL, 4.0 mmol, 7.7 eq).
  • Step 2 ethyl (S)-3-amino-3-(2'-chloro-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3- yl)propanoate
  • ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2'-chloro-4-fluoro-5,6'-dimethyl- [1,1'-biphenyl]-3-yl)propanoate 300 mg, 0.67 mmol, 1.00 eq
  • DCM 9 mL
  • HCl-dioxane 4 M, 9.0 mL, 36.0 mmol, 53.73 eq
  • Step 2 ethyl (S)-3-amino-3-(2'-cyclopropyl-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3- yl)propanoate
  • ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2'-cyclopropyl-4-fluoro-5,6'- dimethyl-[1,1'-biphenyl]-3-yl)propanoate 400 mg, 0.88 mmol, 1.0 eq
  • DCM 9 mL
  • HCl-dioxane 4 M, 9.0 mL, 36.0 mmol, 40.9 eq
  • Step 2 ethyl (S)-3-amino-3-(2'-ethyl-4-fluoro-5,6'-dimethyl-[1,1'-biphenyl]-3- yl)propanoate hydrochloride
  • ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2'-ethyl-4-fluoro-5,6'- dimethyl-[1,1'-biphenyl]-3-yl)propanoate 210 mg, 0.47 mmol, 1.0 eq
  • DCM 2 mL
  • HCl-dioxane 4 M, 3.0 mL, 6.0 mmol, 12.8 eq).
  • Step 2 (S)-ethyl 3-amino-3-(4-fluoro-2'-methoxy-5,6'-dimethylbiphenyl-3-yl)propanoate
  • (S)-ethyl 3-(tert-butoxycarbonylamino)-3-(4-fluoro-2'-methoxy-5,6'- dimethylbiphenyl-3-yl)propanoate (0.96 g, 2.15 mmol, 1.0 eq) in DCM (7 mL) was added HCl-dioxane (4 M, 2.15 mL, 4 eq) and stirred at 25 °C for 2 hours. LCMS showed that the reaction was completed.
  • Step 2 2-methoxy-6-(trifluoromethyl)aniline To a mixture of 1-methoxy-2-nitro-3-(trifluoromethyl)benzene (1.3 g, 5.88 mmol, 1.0 eq) in EtOH (20 mL) was added 10%Pd/C (700 mg) and stirred at room temperature for 16 hours under H 2 atmosphere(2L, 1 atm).
  • Step 4 (S)-ethyl 3-(tert-butoxycarbonylamino)-3-(4-fluoro-2'-methoxy-5-methyl-6'- (trifluoromethyl)biphenyl-3-yl)propanoate
  • 2-bromo-1-methoxy-3-(trifluoromethyl)benzene 400 mg, 1.57 mmol, 1.00 eq
  • (S)-ethyl 3-(tert-butoxycarbonylamino)-3-(2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)propanoate (708 mg, 1.57 mmol, 1.0 eq)
  • K 2 CO 3 650 mg, 4.71 mmol, 3.0 eq
  • Pd(dppf)Cl2 115 mg, 0.157 mmol, 0.1 eq) in dioxane (8 mL) and H 2 O (0.8 mL
  • Step 5 (S)-ethyl 3-amino-3-(4-fluoro-2'-methoxy-5-methyl-6'-(trifluoromethyl)biphenyl- 3-yl)propanoate
  • (S)-ethyl 3-(tert-butoxycarbonylamino)-3-(4-fluoro-2'-methoxy-5- methyl-6'-(trifluoromethyl)biphenyl-3-yl)propanoate 400 mg, 0.8 mmol, 1.00 eq
  • DCM 6 mL
  • HCl-dioxane 4 M, 0.8 mL, 3.2 mmol, 4 eq
  • Step 2 (S)-methyl 3-amino-3-(2',6'-dichloro-4-fluoro-5-methylbiphenyl-3-yl)propanoate
  • methyl (S)-ethyl 3-(tert-butoxycarbonylamino)-3-(2',6'-dichloro-4-fluoro-5- methylbiphenyl-3-yl)propanoate (0.55 g, 1.21 mmol, 1 eq) in DCM (6 mL) was added HCl- dioxane (4 M, 3 mL, 12 mmol, 10 eq). The mixture was stirred at room temperature for 1 hour. LCMS showed that the reaction was completed.
  • Step 2 2-bromo-1-fluoro-3,5-dimethylbenzene
  • 2-fluoro-4,6-dimethylaniline 1.0 g, 7.2 mmol, 1.0 eq
  • CuBr 2 4.8 g, 21.6 mmol, 3.0 eq
  • MeCN MeCN
  • tert-Butyl nitrite 1.68 g, 14.4 mmol, 2.0 eq
  • Step 4 ethyl (S)-3-amino-3-(2',4-difluoro-4',5,6'-trimethyl-[1,1'-biphenyl]-3- yl)propanoate
  • ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2',4-difluoro-4',5,6'- trimethyl-[1,1'-biphenyl]-3-yl)propanoate (720 mg, 1.29 mmol, 1.0 eq) in DCM (2 mL) was added HCl-dioxane (4 M, 2.0 mL, 4.0 mmol, 3.1 eq) and stirred at room temperature for 1 hour.
  • Step 2 (S)-ethyl 3-(tert-butoxycarbonylamino)-3-(2',6'-dichloro-4-fluoro-4',5- dimethylbiphenyl-3-yl)propanoate
  • methyl (S)-ethyl 3-(tert-butoxycarbonylamino)-3-(2-fluoro-3-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate 1.5 g, 3.43 mmol, 1 eq
  • 1,3-dichloro-2-iodo-5-methylbenzene 2.0 g, 6.86 mmol, 2 eq
  • dioxane 10 mL
  • K2CO3 1.9 g, 13.72 mmol, 4 eq
  • Pd(dppf)Cl2 250 mg, 0.343 m
  • Step 3 (S)-ethyl 3-amino-3-(2',6'-dichloro-4-fluoro-4',5-dimethylbiphenyl-3- yl)propanoate
  • methyl (S)-ethyl 3-(tert-butoxycarbonylamino)-3-(2',6'-dichloro-4-fluoro- 4',5-dimethylbiphenyl-3-yl)propanoate 1.3 g, 2.76 mmol, 4 eq
  • DCM 6 mL
  • HCl-dioxane 4 M, 3 mL, 12 mmol, 4.3 eq
  • Step 2 ethyl (S)-3-amino-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate
  • ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(4-fluoro-2',5,6'- trimethyl-[1,1'-biphenyl]-3-yl)propanoate (4.0 g, 9.2 mmol, 1.00 eq) in DCM (6 mL) was added HCl-dioxane (4 M, 4 mL, 16.0 mmol, 1.7 eq).
  • Step 2 ethyl (S)-3-amino-3-(4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3- yl)propanoate
  • ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(4,4'-difluoro-2',5,6'- trimethyl-[1,1'-biphenyl]-3-yl)propanoate 5.5 g, 12.2 mmol, 1.00 eq
  • DCM 6 mL
  • HCl-dioxane 4M, 6 mL, 24.0 mmol, 1.97 eq
  • Step 2 ethyl (S)-3-amino-3-(4'-chloro-4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3- yl)propanoate
  • 2-(4-chloro-2,6-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (544 mg, 2.04 mmol, 1.2 eq)
  • Pd(dppf)Cl 2 62 mg, 0.085 mmol, 0.05 eq
  • K 2 CO 3 7.04 mg, 5.1 mmol, 3.0 eq) in 1,4-dioxane (10 mL) and water (2 mL) was stirred at 110 °C
  • Step 2 ethyl (S)-3-amino-3-(4-fluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3- yl)propanoate
  • ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(4-fluoro-2',4',5,6'- tetramethyl-[1,1'-biphenyl]-3-yl)propanoate 3.1 g, 6.94 mmol, 1.0 eq) in DCM (7 mL) was added HCl-dioxane (4 M, 6.8 mL, 3.9 eq) and stirred at 25 °C for 2 hours.
  • Step 2 2-bromo-1,3-dimethyl-5-(trifluoromethyl)benzene
  • a mixture of 2,6-dimethyl-4-(trifluoromethyl)aniline (793 mg, 4.19 mmol, 1.0 eq), tert-butyl nitrite (0.94 mL, 7.84 mmol, 1.9 eq) and copper(I) bromide (794 mg, 5.53 mmol, 1.3 eq) in anhydrous acetonitrile (16 mL) was stirred at 60 °C for 2 hours under nitrogen atmosphere. LCMS showed that the reaction was completed. The mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo.
  • Step 3 ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4-fluoro-2',5,6'-trimethyl-4'- (trifluoromethyl)-[1,1'-biphenyl]-3-yl)propanoate
  • ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2-fluoro-3-methyl-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (519 mg, 1.15 mmol, 1.0 eq) in dioxane (36 mL) was added 2-bromo-1,3-dimethyl-5-(trifluoromethyl)benzene (306 mg, 1.21 mmol, 1.1 eq), Pd(dppf)Cl2 (188 mg, 0.23 mmol, 0.2 eq), K2CO3 (477 mg
  • Step 5 ethyl (S)-3-amino-3-(4-fluoro-2',5,6'-trimethyl-4'-(trifluoromethyl)-[1,1'- biphenyl]-3-yl)propanoate hydrochloride
  • ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4-fluoro-2',5,6'- trimethyl-4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)propanoate (308 mg, 0.62 mmol, 1.0 eq) in DCM (4 mL) was added HCl-dioxane (4 M, 4.0 mL, 16.0 mmol, 25.8 eq).
  • Step 2 2-bromo-5-cyclopropyl-1,3-dimethylbenzene
  • ACN 4-cyclopropyl-2,6-dimethylaniline
  • H 2 O 1 mL
  • p-toluenesulphonic acid 3.4 g, 19.8 mmo, 4.0 eq
  • the mixture was stirred at 0 °C for 10 mins under under nitrogen atmosphere.
  • a solution of NaNO2 (685.0 mg, 9.93 mmol, 2.0 eq) in H 2 O (2 mL) was added dropwise and the mixture was stirred 0 °C for 30 mins.
  • Step 3 ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4'-cyclopropyl-4-fluoro-2',5,6'- trimethyl-[1,1'-biphenyl]-3-yl)propanoate
  • Step 4 ethyl (S)-3-amino-3-(4'-cyclopropyl-4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3- yl)propanoate hydrochloride
  • ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4'-cyclopropyl-4-fluoro- 2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate 900 mg, 1.91 mmol, 1.0 eq
  • DCM 5 mL
  • HCl-dioxane 4 M, 5.0 mL, 20.0 mmol, 10.47 eq
  • Step 2 ethyl (S)-3-amino-3-(4-fluoro-4'-methoxy-2',5,6'-trimethyl-[1,1'-biphenyl]-3- yl)propanoate hydrochloride
  • ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4-fluoro-4'-methoxy- 2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate 200 mg, 0.43 mmol, 1.0 eq
  • DCM 7 mL
  • HCl-dioxane 4 M, 2.0 mL, 4.0 mmol, 9.3 eq).
  • Step 2 ethyl (S)-3-amino-3-(4'-cyano-4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3- yl)propanoate
  • ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4'-cyano-4-fluoro-2',5,6'- trimethyl-[1,1'-biphenyl]-3-yl)propanoate (320 mg, 0.7 mmol, 1.0 eq) in DCM (2 mL) was added HCl-dioxane (4 M, 2.0 mL, 4.0 mmol, 5.7 eq).
  • Step 2 ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4'-((dimethylamino)methyl)-4- fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate
  • a mixture of ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4-fluoro-4'-formyl-2',5,6'- trimethyl-[1,1'-biphenyl]-3-yl)propanoate (1.3 g, 2.8 mmol, 1.0 eq) and dimethylamine hydrochloride (233 mg, 2.9 mmol, 1.05 eq) in DCE (10 mL) was stirred at room temperature for 30 mins.
  • Step 3 ethyl (S)-3-amino-3-(4'-((dimethylamino)methyl)-4-fluoro-2',5,6'-trimethyl-[1,1'- biphenyl]-3-yl)propanoate
  • ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4'- ((dimethylamino)methyl)-4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate 800 mg, 1.64 mmol, 1.0 eq
  • DCM 10 mL
  • HCl-dioxane 4 M, 3mL, 12.0 mmol
  • Step 2 ethyl (S)-3-amino-3-(4-fluoro-4'-((3-fluoroazetidin-1-yl)methyl)-2',5,6'- trimethyl-[1,1'-biphenyl]-3-yl)propanoate
  • ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(4-fluoro-4'-((3-fluoroazetidin-1- yl)methyl)-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate 800 mg, 1.5 mmol, 1.0 eq
  • DCM 10 mL
  • HCl-dioxane 4M, 10.0 mL, 40.0 mmol, 26.7 eq
  • Step 2 ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2'-chloro-4-fluoro-4',5,6'-trimethyl- [1,1'-biphenyl]-3-yl)propanoate
  • 2-bromo-1-chloro-3,5-dimethylbenzene (483 mg, 2.2 mmol, 1.10 eq)
  • ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)propanoate (902 mg, 2.0 mmol, 1.00 eq) in dioxane (10 mL) under nitrogen atmosphere was added a solution of K2CO3 (552 mg, 4.0 mmol, 2.00 eq) in H 2 O (5 mL) and Pd(dppf)C
  • Step 3 ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2'-cyclopropyl-4-fluoro-4',5,6'- trimethyl-[1,1'-biphenyl]-3-yl)propanoate
  • cyclopropylboronic acid (327 mg, 3.8 mmol, 2.00 eq) in toluene (10 mL) under nitrogen atmosphere was added a solution of K3PO4 (807 mg, 3.8 mmol, 2.00 eq) in H 2 O (2 m
  • Step 4 ethyl (S)-3-amino-3-(2'-cyclopropyl-4-fluoro-4',5,6'-trimethyl-[1,1'-biphenyl]-3- yl)propanoate hydrochloride
  • ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(2'-cyclopropyl-4-fluoro-4',5,6'- trimethyl-[1,1'-biphenyl]-3-yl)propanoate 250 mg, 0.53 mmol, 1.00 eq
  • 1,4-dioxane 6 mL
  • HCl-dioxane 4M4.0 mL, 16.0 mmol, 30.2 eq
  • Step 2 (2-bromo-6-fluoro-3-methylphenyl)methanol
  • 2-bromo-6-fluoro-3-methylbenzaldehyde (3.0 g, 13.8 mmol, 1.00 eq) in MeOH (30 mL) under nitrogen atmosphere was added NaBH 4 (1.5 g, 41.4 mmol, 3.00 eq) at 0°C and stirred at room temperature for 2 hours.
  • the mixture was quenched with water (50 mL), extracted with EtOAc (50 mL x 3).
  • Step 3 (2-bromo-3-(bromomethyl)-4-fluoro-1-methylbenzene
  • PBr 3 (3 mL, 29.2 mmol, 2.00 eq) at room temperature and stirred for 1 hour.
  • the reaction mixture was concentrated in vacuo and the residue was purified by silica gel column (pet ether: EtOAc 99:1) to provide 2-bromo-3- (bromomethyl)-4-fluoro-1-methylbenzene as a white solid (3.58 g).
  • Step 5 ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(3',4-difluoro-2',5,6'-trimethyl-[1,1'- biphenyl]-3-yl)propanoate
  • 2-bromo-4-fluoro-1,3-dimethylbenzene 800 mg, 3.93 mmol, 1.00 eq
  • Step 6 ethyl (S)-3-amino-3-(3',4-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3- yl)propanoate hydrochloride
  • ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(3',4-difluoro-2',5,6'- trimethyl-[1,1'-biphenyl]-3-yl)propanoate 1.2 g, 2.68 mmol, 1.00 eq
  • 1,4-dioxane 6 mL
  • HCl-dioxane 4M 4.0 mL, 16.0 mmol, 5.97 eq).
  • Step 2 1-methoxy-2,4-dimethyl-3-nitrobenzene To a mixture of 1-bromo-2,4-dimethyl-3-nitrobenzene (8 g, 35 mmol, 1.0 eq) in MeOH (80 mL) and DMF (80 mL) was added NaOCH3 (5.67 g, 105 mmol, 3 eq) and CuBr (1 g, 7 mmol, 0.2 eq) at room temperature. The mixture was stirred at 110°C for 16 hours. The reaction mixture was filtered. The filtrate was diluted with water (100 mL), extracted with EtOAc (100 mL x 3).
  • Step 3 3-methoxy-2,6-dimethylaniline
  • MeOH 60 mL
  • H 2 O 6 mL
  • NH4Cl 5.18 g, 96 mmol, 3.0 eq
  • Zn 20.8 g, 320 mmol, 10 eq
  • Step 4 2-bromo-4-methoxy-1,3-dimethylbenzene To a mixture of 3-methoxy-2,6-dimethylaniline (2 g, 13.24 mmol, 1.0 eq) in MeCN (30 mL) was added t-BuONO (2.06 g, 20 mmol, 1.5 eq) at 0°C, then CuBr(2.27 g, 15.89 mmol, 1.2 eq) was added.
  • Step 5 (S)-ethyl 3-(tert-butoxycarbonylamino)-3-(4-fluoro-3'-methoxy-2',5,6'- trimethylbiphenyl-3-yl)propanoate
  • 2-bromo-4-methoxy-1,3-dimethylbenzene 700 mg, 3.27 mmol, 1.00 eq
  • (S)- ethyl 3-(tert-butoxycarbonylamino)-3-(2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)propanoate (1.47 g, 3.27 mmol, 1.0 eq)
  • K 2 CO 3 (1.35 g, 9.81 mmol, 3 eq)
  • Pd(dppf)Cl 2 239 mg, 0.327 mmol, 0.1 eq) in dioxane (10 mL) and H 2 O (1 mL)
  • Step 2 ethyl (S)-3-amino-3-(6'-cyano-4-fluoro-2',3',5-trimethyl-[1,1'-biphenyl]-3- yl)propanoate
  • ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(6'-cyano-4-fluoro- 2',3',5-trimethyl-[1,1'-biphenyl]-3-yl)propanoate 500 mg, 1.1 mmol, 1.0 eq
  • DCM 10 mL
  • HCl-dioxane 4 M, 10 mL, 40.0 mmol, 36.4 eq
  • Step 2 (S)-ethyl 3-amino-3-(3',4-difluoro-2',4',5,6'-tetramethylbiphenyl-3-yl)propanoate
  • methyl (S)-methyl 3-(tert-butoxycarbonylamino)-3-(3',4-difluoro-2',4',5,6'- tetramethylbiphenyl-3-yl)propanoate 500 mg, 1.12 mmol, 1 eq
  • DCM 6 mL
  • HCl-dioxane 4 M, 3 mL, 12 mmol, 10 eq
  • Step 2 ethyl (S)-3-(5-bromo-3-chloro-2-fluorophenyl)-3-(((R)-tert- butylsulfinyl)amino)propanoate
  • chlorotrimethylsilane 888 mg, 8.22 mmol, 0.2 eq
  • Step 2 ethyl (S)-3-amino-3-(5-chloro-4-fluoro-2',6'-dimethyl-[1,1'-biphenyl]-3- yl)propanoate
  • ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(5-chloro-4-fluoro-2',6'- dimethyl-[1,1'-biphenyl]-3-yl)propanoate (3.0 g, 43.66 mmol, 1.0 eq) in DCM (20 mL) was added HCl-dioxane (4 M, 20 mL, 80 mmol, 1.8 eq).
  • Step 2 ethyl (S)-3-amino-3-(5-chloro-4,4'-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3- yl)propanoate
  • ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(5-chloro-4,4'-difluoro-2',6'- dimethyl-[1,1'-biphenyl]-3-yl)propanoate 1.2 g, 2.54 mmol, 1.0 eq
  • DCM 6 mL
  • HCl-dioxane 4 M, 3 mL, 12 mmol, 4.7 eq
  • Step 2 ethyl (S)-3-amino-3-(5-chloro-4-fluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-3- yl)propanoate
  • ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(5-chloro-4-fluoro-2',4',6'- trimethyl-[1,1'-biphenyl]-3-yl)propanoate (1.9 g, 4.06 mmol, 1.0 eq) in DCM (20 mL) was added HCl-dioxane (4 M, 3 mL, 12 mmol, 3.0 eq).
  • Step 2 ethyl (S)-3-(5-bromo-2,3-difluorophenyl)-3-(((R)-tert- butylsulfinyl)amino)propanoate
  • chlorotrimethylsilane 267 mg, 2.46 mmol, 0.2 eq
  • Step 2 ethyl (S)-3-amino-3-(4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate
  • ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(4,5-difluoro-2',6'-dimethyl- [1,1'-biphenyl]-3-yl)propanoate 900 mg, 2.06 mmol, 1.0 eq) in DCM (4 mL) was added HCl-dioxane (4 M, 2 mL, 8.0 mmol, 3.88 eq).
  • Step 2 ethyl (S)-3-amino-3-(4,4',5-trifluoro-2',6'-dimethyl-[1,1'-biphenyl]-3- yl)propanoate
  • ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(4,4',5-trifluoro-2',6'-dimethyl- [1,1'-biphenyl]-3-yl)propanoate 1.0 g, 2.2 mmol, 1.0 eq
  • DCM 4 mL
  • HCl- dioxane 4 M, 2 mL, 4.0 mmol, 1.8 eq
  • Step 2 ethyl (S)-3-amino-3-(4,5-difluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-3- yl)propanoate
  • ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(4,5-difluoro-2',4',6'-trimethyl- [1,1'-biphenyl]-3-yl)propanoate 1.g, 3.1 mmol, 1.0 eq
  • DCM 20 mL
  • HCl- dioxane 4 M, 2 mL, 8.0 mmol, 2.58 eq).
  • Step 3 ethyl (S)-3-(5-bromo-2-fluoro-3-(trifluoromethyl)phenyl)-3-(((R)-tert- butylsulfinyl)amino)propanoate
  • chlorotrimethylsilane 465 mg, 4.28 mmol, 0.2 eq
  • the reaction was purged with N2 for 5 min, followed by addition of PdCl2(dppf) (0.712 g, 0.973 mmol) and another N2 purge for 1 min.
  • the reaction was stirred at 70C for 4 hours.
  • the reaction mixture was diluted into 250 mL EtOAc, then washed with 1N HCl (250 mL), Sat. NaHCO 3 (205 mL) and Brine (250 mL).
  • Step 2 (S)-ethyl 3-amino-3-(4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)biphenyl-3- yl)propanoate
  • (S)-ethyl 3-((R)-1,1-dimethylethylsulfinamido)-3-(4-fluoro-2',6'-dimethyl-5- (trifluoromethyl)biphenyl-3-yl)propanoate (0.93 g, 1.9 mmol, 1.00 eq) in DCM (8 mL) was added HCl-dioxane (4M, 1.9 mL, 7.6 mmol, 4 eq) and stirred at room temperature for 2 hours.
  • Step 2 ethyl 2-(5-((dimethylamino)methyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate
  • Step 3 2-(5-((dimethylamino)methyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoic acid
  • Ethyl 2-(5-((dimethylamino)methyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate 300 mg, 1.02 mmol
  • LiOH-H 2 O 120 mg, 3.02 mmol
  • Step 3 ethyl 2-(4-((dimethylamino)methyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate
  • Step 4 2-(4-((dimethylamino)methyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoic acid
  • Ethyl 2-(4-((dimethylamino)methyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (100 mg, 0.33 mmol) was treated with LiOH-H 2 O (40 mg, 1.01 mmol) in methanol (2 mL) and water (1 mL) at room temperature for 2 hours.
  • Step 2 ethyl 2-(5-((3, 3-difluoroazetidin-1-yl)methyl)-2-oxopyridin-1(2H)-yl)-4- methylpentanoate
  • a mixture of 5-((3,3-difluoroazetidin-1-yl)methyl)pyridin-2(1H)-one (248 mg, 1.24 mmol), ethyl 4-methyl-2-(methylsulfonyloxy)pentanoate (443 mg, 1.86 mmol) and K2CO3 (514 mg, 3.72 mmol) in MeCN (5 mL) was stirred at 80 °C overnight. The mixture was filtered and washed with MeCN (5 mL).
  • Step 3 2-(5-((3, 3-difluoroazetidin-1-yl)methyl)-2-oxopyridin-1(2H)-yl)-4- methylpentanoic acid
  • Ethyl 2-(5-((3,3-difluoroazetidin-1-yl)methyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate 151 mg, 0.44 mmol
  • LiOH-H 2 O 28 mg, 0.66 mmol
  • H 2 O 0.5 mL
  • Step 1 ethyl 2-(5-formyl-2-oxopyridin-1(2H)-yl)-4-methylpentanoate
  • 6-oxo-1,6-dihydropyridine-3-carbaldehyde 400 mg, 3.2 mmol
  • ethyl 4-methyl- 2-(methylsulfonyloxy)pentanoate 1 g, 4.2 mmol
  • K2CO3 1.1 g, 8 mmol
  • Step 2 ethyl 2-(5-((3-fluoroazetidin-1-yl)methyl)-2-oxopyridin-1(2H)-yl)-4- methylpentanoate
  • a mixture of ethyl 2-(5-formyl-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (300 mg, 1.13 mmol) and 3-fluoroazetidine hydrochloride (251 mg, 2.26 mmol) in DCE (4 mL) was stirred at room temperature for 30 mins.
  • Sodium triacetoxyborohydride (959 mg, 4.52 mmol) was added and stirred at room temperature overnight.
  • Step 3 2-(5-((3-fluoroazetidin-1-yl)methyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoic acid
  • Ethyl 2-(5-((3-fluoroazetidin-1-yl)methyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (264 mg, 0.81 mmol) was treated with LiOH-H 2 O (171 mg, 4 mmol) in EtOH (4 mL) and H 2 O (1 mL) at room temperature for 2 hours. The mixture was acidified to pH 4 ⁇ 5 with 1N HCl.
  • Step 1 ethyl 4-methyl-2-(5-(morpholinomethyl)-2-oxopyridin-1(2H)-yl)pentanoate
  • ethyl 2-(5-formyl-2-oxopyridin-1(2H)-yl)-4-methylpentanoate 300 mg, 1.13 mmol
  • morpholine 147 mg, 1.70 mmol
  • Step 2 4-methyl-2-(5-(morpholinomethyl)-2-oxopyridin-1(2H)-yl)pentanoic acid
  • Ethyl 4-methyl-2-(5-(morpholinomethyl)-2-oxopyridin-1(2H)-yl)pentanoate (150 mg, 0.45 mmol) was treated with LiOH-H 2 O (56 mg, 1.34 mmol) in THF (3 mL) and H 2 O (0.5 mL) at room temperature for 2 hours. The mixture was acidified to pH 4 ⁇ 5 with 1N HCl.
  • Step 2 2-(5-(((R)-3-fluoropyrrolidin-1-yl)methyl)-2-oxopyridin-1(2H)-yl)-4- methylpentanoic acid
  • Ethyl 2-(5-(((R)-3-fluoropyrrolidin-1-yl)methyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (426 mg, 1.13 mmol) was treated with LiOH-H 2 O (237 mg, 5.65 mmol) in EtOH (6 mL) and H 2 O (0.6 mL) at room temperature for 2 hours. The mixture was acidified to pH 4 ⁇ 5 with 1N HCl.
  • Step 2 ethyl 2-(5-(3-(dimethylamino)azetidin-1-yl)-4-methyl-2-oxopyridin-1(2H)-yl)-4- methylpentanoate
  • N,N-dimethylazetidin-3-amine dihydrochloride (1.57 g, 9.07 mmol, 1.5 eq)
  • CsCO 3 8.0 g, 24.5 mmol, 4.0 eq
  • BINAP 376 mg, 0.606 mmol, 0.1 eq
  • Pd2dba3 250 mg, 0.27 mmol, 0.05 eq
  • Step 3 2-(5-(3-(dimethylamino)azetidin-1-yl)-4-methyl-2-oxopyridin-1(2H)-yl)-4- methylpentanoic acid
  • Ethyl 2-(5-(3-(dimethylamino)azetidin-1-yl)-4-methyl-2-oxopyridin-1(2H)-yl)-4- methylpentanoate(1.4 g, 4.0 mmol, 1.0 eq) was treated with LiOH-H 2 O (840 mg, 20.0 mmol, 5.0 eq) in THF (20 mL) and water (6 mL) at room temperature for 2 hours.
  • the MeOH was removed and the aqueous material acidified with 1N HCl to pH 4.
  • the mixture was purified by reverse phase HPLC in neutral condition (A: water, B: MeOH, 60%B) to provide 2-(5-(3- (dimethylamino)azetidin-1-yl)-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentanoic acid as a white solid (800 mg).
  • Step 2 5-((dimethylamino)methyl)-4-(trifluoromethyl)pyridin-2-ol
  • Step 3 ethyl 2-(5-((dimethylamino)methyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)- 4-methylpentanoate
  • 5-((dimethylamino)methyl)-4-(trifluoromethyl)pyridin-2-ol) 150 mg, 0.68 mmol
  • ethyl 4-methyl-2-(methylsulfonyloxy)pentanoate (194 mg, 0.816 mmol) and K 2 CO 3 (281.5 mg, 2.04 mmol) in MeCN (10 mL) was stirred at 80°C overnight.
  • Step 4 2-(5-((dimethylamino)methyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4- methylpentanoic acid
  • Ethyl 2-(5-((dimethylamino)methyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4- methylpentanoate (170 mg, 0.47 mmol) was treated with LiOH-H 2 O (98.7 mg, 2.35 mmol) in MeOH (10 mL) and H 2 O (2 mL) at room temperature for 2 hours.
  • the mixture was acidified to pH 4 ⁇ 5 with 1N HCl and purified by reverse phase HPLC on a C18/40 g column (A: water 10 mM NH4HCO3, B: MeOH, 0 ⁇ 100%) to provide 2-(5-((dimethylamino)methyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid as white solid (120 mg). Yield 76% (ESI 335.2 (M+H) + ).
  • Step 2 2-(6-oxo-1,6-dihydropyridin-3-yl)acetaldehyde 5-(2-methoxyvinyl)pyridin-2(1H)-one (1.2 g, 7.95 mmol) was treated with HCOOH (20 mL) at 70°C for 2 hours. The solvent was removed in vacuo to provide the crude product 2-(6- oxo-1,6-dihydropyridin-3-yl)acetaldehyde as a red oil (0.8 g, crude). (ESI 138.3 (M+H) + ).
  • Step 3 5-(2-(dimethylamino)ethyl)pyridin-2(1H)-one
  • Step 4 ethyl 2-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate
  • Step 5 2-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoic acid
  • Ethyl 2-(5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (100 mg, 0.32 mmol) was treated with LiOH-H 2 O (54 mg, 1.28 mmol) in EtOH (3 mL) and H 2 O (1 mL) at room temperature for 2 hours.
  • the reaction mixture was acidified to pH 4 ⁇ 5 with 1 N HCl.
  • Step 2 ethyl 2-(4-(2-(benzyloxycarbonylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4- methylpentanoate
  • ethyl 2-(4-bromo-2-oxopyridin-1(2H)-yl)-4-methylpentanoate 1.6 g, 5.0 mmol
  • potassium benzyl N-[2-(trifluoroboraly)ethyl]carbamate (1.71 g, 6 mmol)
  • Pd(dppf)Cl2 366 mg, 0.5 mmol
  • Na2CO3 (1.06 g, 10 mmol
  • reaction was concentrated and purified by reverse phase HPLC on a C18/40 g column (A: water/0.01%TFA, B: MeOH, 0 ⁇ 100%) to provide ethyl 2-(4-(2- (benzyloxycarbonylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate as a yellow oil (700 mg). Yield 35% (ESI 415.1 (M+H) + ).
  • Step 3 ethyl 2-(4-(2-aminoethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate
  • Ethyl 2-(4-(2-(benzyloxycarbonylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (0.7 g, 1.7 mmol) was treated with TFA (10 mL) at 50°C for 4 hours.
  • Step 4 ethyl 2-(4-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate
  • MeOH MeOH
  • HCHO 37% in H 2 O, 1 mL
  • NaBH(OAc)3 (1.21 g, 5.72 mmol) was added and stirred at room temperature for 1 hour.
  • Step 5 2-(4-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoic acid
  • Ethyl 2-(4-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (400 mg, 1.3 mmol) was treated with LiOH-H 2 O (218 mg, 5.2 mmol) in MeOH (4 mL) and H 2 O (1 mL) at room temperature for 1 hour. The mixture was acidified to pH 4 ⁇ 5 with 1N HCl.
  • Step 2 ethyl 2-(3-(2-(benzyloxycarbonylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4- methylpentanoate
  • ethyl 2-(3-bromo-2-oxopyridin-1(2H)-yl)-4-methylpentanoate 1 g, 3.17 mmol
  • potassium benzyl N-[2-(trifluoroboryl)ethyl]carbamate (1.08 g, 3.8 mmol)
  • Pd(dppf)Cl2 36 mg, 0.16 mmol
  • Cs2CO3 (2 g, 6.34 mmol
  • RuPhos 144 mg , 0.32 mmol
  • Step 3 ethyl 2-(3-(2-aminoethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate
  • Ethyl 2-(3-(2-(benzyloxycarbonylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (1.07 g, 2.58 mmol) was treated with TFA (20 mL) at 50 °C for 4 hours.
  • Step 4 ethyl 2-(3-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate
  • MeOH MeOH
  • HCHO 37% in H 2 O, 1 mL
  • NaBH(OAc) 3 (1.81 g, 8.56 mmol) was added and stirred at room temperature for 1 hour.
  • Step 5 2-(3-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoic acid
  • Ethyl 2-(3-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (600 mg, 1.95 mmol) was treated with LiOH monohydrate (328 mg, 7.8 mmol) in EtOH (4 mL) and H 2 O (1 mL) at room temperature for 1 hour. The mixture was acidified to pH 4 ⁇ 5 with 1N HCl aqueous solution.
  • Step 2 ethyl 2-(5-(2-(azetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate
  • 5-(2-(azetidin-1-yl)ethyl)pyridin-2(1H)-one 800 mg, 4.49 mmol
  • ethyl 4- methyl-2-(methylsulfonyloxy)pentanoate 2.2 g, 6.74 mmol
  • K2CO3 1.8 g, 13.47 mmol
  • Step 3 2-(5-(2-(azetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoic acid
  • Ethyl 2-(5-(2-(azetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (600 mg, 1.88 mmol) was treated with LiOH-H 2 O (394 mg, 9.40 mmol) in THF (10 mL) and H 2 O (2 mL) at room temperature for 1 hour. The mixture was acidified to pH 4 ⁇ 5 with 1N HCl.
  • Step 2 ethyl 2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4- methylpentanoate
  • 5-(2-(3-fluoroazetidin-1-yl)ethyl)pyridin-2(1H)-one 1.9 g, 9.7 mmol
  • ethyl 4- methyl-2-(methylsulfonyloxy)pentanoate (3.45 g, 14.5 mmol)
  • Cs 2 CO 3 9.5 g, 29.1 mmol
  • Step 3 2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoic acid
  • Ethyl 2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate 650 mg, 1.92 mmol) was treated with LiOH-H 2 O (322 mg, 7.68 mmol) in MeOH (10 mL) and H 2 O (2.5 mL) at room temperature for 2 hours.
  • the mixture was acidified to pH 4 ⁇ 5 with 1N HCl, purified by reverse phase HPLC on a C18/40 g column (A: water 10 mM NH4HCO3, B: MeOH, 0 ⁇ 100%) to provide 2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4- methylpentanoic acid as a white solid (350 mg). Yield 59% (ESI 311.2(M+H) + ).
  • Step 1 (S)-2-bromo-3-cyclopropylpropanoic acid To a solution of (S)-2-amino-3-cyclopropylpropanoic acid (5.0 g, 38.7 mmol) in H 2 O (50 mL) was added 40% HBr (60 mL). The reaction mixture was stirred at 0 °C for 10 min. A solution of sodium nitrite (4.5 g, 24 mmol) in H 2 O (10 mL) was added.
  • Step 2 ethyl (S)-2-bromo-3-cyclopropylpropanoate To a solution of (S)-2-bromo-3-cyclopropylpropanoic acid (1 g, 5.2 mmol) in EtOH (20 mL) was added SOCl 2 (1.8 g, 15.6 mmol) and stirred at ambient temperature for 2 hours. The solvent was removed in vacuo to provide ethyl 2-bromo-3-cyclopropylpropanoate as a white solid (1.2 g, crude) used directly in the next reaction. (ESI 221.0 (M+H) + ).
  • Step 3 ethyl 3-cyclopropyl-2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)- yl)propanoate
  • a mixture of ethyl 2-bromo-3-cyclopropylpropanoate (800 mg, 3.64 mmol), 5-(2-(3- fluoroazetidin-1-yl)ethyl)pyridin-2(1H)-one (1.07 g, 5.46 mmol) and K2CO3 (1.5 g, 10.92 mmol) in MeCN (10 mL) was stirred at 80 °C overnight.
  • Step 4 3-cyclopropyl-2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)- yl)propanoic acid
  • Ethyl 3-cyclopropyl-2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)propanoate 400 mg, 1.20 mmol
  • LiOH-H 2 O 201 mg, 4.80 mmol
  • EtOH 4 mL
  • H 2 O (1 mL
  • Step 2 ethyl 2-(5-allyl-2-oxopyridin-1(2H)-yl)-4-methylpentanoate
  • Step 3 ethyl 4-methyl-2-(2-oxo-5-(2-oxoethyl)pyridin-1(2H)-yl)pentanoate
  • a solution of ethyl 2-(5-allyl-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (7.1 g, 25.6 mmol) in THF/H 2 O (80 mL/30 mL) was added a solution of K 2 OsO 4 -2H 2 O (94.0 mg, 0.26 mmol) in H 2 O (4 mL) and stirred at room temperature for 1 h.
  • Step 4 ethyl 2-(5-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4- methylpentanoate
  • ethyl 4-methyl-2-(2-oxo-5-(2-oxoethyl)pyridin-1(2H)-yl)pentanoate 7.0 g, 25.0 mmol
  • DCE 70 mL
  • R 3-fluoropyrrolidine hydrochloride
  • Step 5 2-(5-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4- methylpentanoic acid
  • Ethyl 2-(5-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (1.3 g, 3.69 mmol) was treated with LiOH-H 2 O (775.0 mg, 18.4 mmol) in MeOH (12 mL) and water (5 mL) at room temperature for 2 hours. The MeOH was removed in vacuo, acidified with 1N HCl to pH 5.
  • Step 2 2-(6-methoxy-4-methylpyridin-3-yl)acetaldehyde
  • E 2-(6-methoxy-4-methylpyridin-3-yl)acetaldehyde
  • TFA 20 mL
  • the solvent was removed in vacuo to provide 2-(6- methoxy-4-methylpyridin-3-yl)acetaldehyde as a red oil (1.5 g, crude) used without further purification.
  • Step 3 2-(6-methoxy-4-methylpyridin-3-yl)-N,N-dimethylethanamine
  • 2-(6-methoxy-4-methylpyridin-3-yl)acetaldehyde (1.45 g, 8.78 mmol)
  • dimethylamine (2M in THF, 17.5 mL, 35.72 mmol)
  • AcOH 0.8 g, 13.2 mmol
  • DCE 30 mL
  • Step 4 5-(2-(dimethylamino)ethyl)-4-methylpyridin-2-ol A mixture of 2-(6-methoxy-4-methylpyridin-3-yl)-N,N-dimethylethylamine (850 mg, 4.38 mmol) in HBr/AcOH (20 mL) was heated at 75°C for 16 h.
  • Step 5 ethyl 2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4- methylpentanoate
  • 5-(2-(dimethylamino)ethyl)-4-methylpyridin-2-ol 650 g, 3.6 mmol
  • ethyl 4- methyl-2-(methylsulfonyloxy)pentanoate (1.71 g, 7.2 mmol)
  • K 2 CO 3 (1.49 g, 10.8 mmol
  • Step 6 2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4- methylpentanoic acid
  • Ethyl 2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (500 mg, 1.55 mmol) was treated with LiOH-H 2 O (260 mg, 6.2 mmol) in MeOH (10 mL) and H 2 O (2 mL) at room temperature for 2 hours.
  • the mixture was acidified to pH 4 ⁇ 5 with 1N HCl and purified by reverse phase HPLC on a C18/40 g column (A: water 10 mM NH 4 HCO 3, B: MeOH, 0 ⁇ 100%) to provide 2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)- yl)-4-methylpentanoic acid as a white solid (420 mg). Yield 92% (ESI 295.2(M+H) + ).
  • Step 2 ethyl 2-bromo-5-methylhexanoate To a mixture of (R)-2-bromo-5-methylhexanoic acid (30 g, 144 mmol) in EtOH (200 mL) at 0°C was added SOCl2 (86 g, 720 mmol). The mixture was stirred for 4 h at room temperature.
  • Step 3 ethyl 2-(5-bromo-4-methyl-2-oxopyridin-1(2H)-yl)-5-methylhexanoate A mixture of 5-bromo-4-methylpyridin-2(1H)-one (8 g, 42.78 mmol), Cs 2 CO 3 (27.9 g, 85.56 mmol) and ethyl 2-bromo-5-methylhexanoate (15 g, 64.17 mmol) in toluene (160 mL) was stirred at 110 oC for 4hours.
  • Step 4 (E)-ethyl 2-(5-(2-ethoxyvinyl)-4-methyl-2-oxopyridin-1(2H)-yl)-5- methylhexanoate A mixture of ethyl 2-(5-bromo-4-methyl-2-oxopyridin-1(2H)-yl)-5-methylhexanoate (5.4 g, 15.7 mmol), (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.22 g, 31.4 mmol), Pd(PPh3)4 (912 mg, 0.79 mmol) and K2CO3 (4.33 g, 31.4 mmol) in 1,4-dioxane (70 mL) and water (7 mL) was stirred at 70 ⁇ under N2 for 20 h.
  • Step 5 ethyl 5-methyl-2-(4-methyl-2-oxo-5-(2-oxoethyl)pyridin-1(2H)-yl)hexanoate
  • E ethyl 2-(5-(2-ethoxyvinyl)-4-methyl-2-oxopyridin-1(2H)-yl)-5-methylhexanoate (3.8 g, 11.34 mmol) was treated with TFA (40 mL) at room temperature for 1 hour.
  • Step 6 ethyl 2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-5- methylhexanoate
  • DCM dimethylamine
  • Step 7 2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-5- methylhexanoic acid
  • Ethyl 2 - (5- (2- (dimethylamino)ethyl) - 4-methyl – 2 – oxopyridin - 1(2H) - yl) – 5 - methylhexanoate (1.4 g, 4.17 mmol) was treated with LiOH-H 2 O (700 mg, 16.68 mmol) in MeOH (20 mL) and H 2 O (4 mL) at room temperature for 2 hours.
  • the reaction mixture was acidified to pH 4 ⁇ 5 with 1 N HCl.
  • Step 2 ethyl 2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4- methylpentanoate
  • Step 3 2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4- methylpentanoic acid
  • Step 2 ethyl 4-methyl-2-(4-methyl-2-oxo-5-(2-oxoethyl)pyridin-1(2H)-yl)pentanoate
  • ethyl 2-(5-allyl-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentanoate 1.6 g, 5.49 mmol
  • THF/H 2 O 20 mL/10 mL
  • K2OsO4-2H 2 O 20 mg, 0.055 mmol
  • Step 3 ethyl 2-(5-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)- yl)-4-methylpentanoate
  • a mixture of ethyl 4-methyl-2-(4-methyl-2-oxo-5-(2-oxoethyl)pyridin-1(2H)-yl)pentanoate 950 mg, 3.24 mmol
  • (R)-3-fluoropyrrolidine hydrochloride 814 mg, 6.48 mmol
  • Step 4 2-(5-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4- methylpentanoic acid
  • Ethyl 2-(5-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4- methylpentanoate (550 mg, 1.50 mmol) was treated with LiOH-H 2 O (120 mg, 4.50 mmol) in THF (6 mL) and water (2 mL) at room temperature for 2 hours. The reaction was acidified with 1N HCl to pH 8.
  • Step 2 2-(6-methoxy-4-(trifluoromethyl)pyridin-3-yl)acetaldehyde To a solution of (E)-2-methoxy-5-(2-methoxyvinyl)-4-(trifluoromethyl)pyridine (450 mg, 1.930 mmol) in DCM (29.689 mL) was added TFA (0.595 mL, 7.72 mmol) and water (0.591 mL, 32.8 mmol). The reaction was stirred for 18 hrs at 45 °C. The reaction was diluted with DCM and quenched with NaHCO 3 .
  • Step 3 5-(2-(azetidin-1-yl)ethyl)-2-methoxy-4-(trifluoromethyl)pyridine
  • azetidine hydrochloride 3.4 g, 36.2 mmol
  • NaBH(OAc) 3 7.7 g, 36.2 mmol
  • Step 4 5-(2-(azetidin-1-yl)ethyl)-4-(trifluoromethyl)pyridin-2(1H)-one A mixture of 5-(2-(azetidin-1-yl)ethyl)-2-methoxy-4-(trifluoromethyl)pyridine (2.95 g, 11.3 mmol) in HBr/AcOH (20 mL) was stirred at 50oC for 5 h.
  • reaction mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC on a C18/80 g column (A: water 10 mM NH 4 HCO 3 , B: MeOH, 0 ⁇ 100%) to provide 5-(2-(azetidin-1- yl)ethyl)-4-(trifluoromethyl)pyridin-2(1H)-one as a yellow oil (710 mg). Yield 25% (ESI 247.1(M+H) + ).
  • Step 5 ethyl 2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4- methylpentanoate
  • 5-(2-(azetidin-1-yl)ethyl)-4-(trifluoromethyl)pyridin-2(1H)-one 710 mg, 2.9 mmol
  • MeCN MeCN
  • ethyl 4-methyl-2-(methylsulfonyloxy)pentanoate 1.1 g, 4.4 mmol
  • K2CO3 1.2 g, 8.7 mmol
  • reaction mixture was stirred at 80oC for 16 hours.
  • the reaction mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC on a C18/40 g column (A: water 10 mM NH 4 HCO 3 , B: MeOH, 0 ⁇ 100%) to provide ethyl 2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- 1(2H)-yl)-4-methylpentanoate as a yellow oil (500 mg). Yield 44% (ESI 389.2(M+H) + ).
  • Step 6 2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4- methylpentanoic acid
  • Step 2 5-(2-(dimethylamino)ethyl)-4-(trifluoromethyl)pyridin-2(1H)-one HBr (33% in Acetic Acid) (4.04 mL, 24.57 mmol) was added to 2-(6-methoxy-4- (trifluoromethyl)pyridin-3-yl)-N,N-dimethylethan-1-amine (0.305 g, 1.229 mmol) and heated to 75 °C in a pressure vessel.
  • Step 4 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4- methylpentanoic acid
  • Ethyl 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4- methylpentanoate (390 mg, 1.0 mmol) was treated with LiOH monohydrate (435 mg, 10.36 mmol) in EtOH (10 mL) and H 2 O (1 mL) at room temperature for 1 hour. The mixture was acidified to pH 4 ⁇ 5 with 1N HCl aqueous solution.
  • reaction mixture was stirred at 80oC for 16 h.
  • the reaction mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC on a C18/40 g column (A: water 10 mM NH4HCO3, B: MeOH, 0 ⁇ 100%) to provide ethyl 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-3- methylbutanoate as a yellow oil (2.6 g). Yield 69% (ESI 363.2(M+H) + ).
  • Step 2 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-3- methylbutanoic acid
  • Ethyl 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-3- methylbutanoate (2.6 g, 7.1 mmol) was treated with LiOH-H 2 O (1.47 g, 35 mmol) in EtOH (15 mL) and water (3 mL) at room temperature for 2 h.
  • reaction mixture was neutralized with 2 N HCl, concentrated in vacuo and the residue was purified by reverse phase HPLC on a C18/40 g column (A: water 10 mM NH 4 HCO 3 , B: MeOH, 0 ⁇ 100%) to provide 2-(5-(2- (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-3-methylbutanoic acid as a yellow oil (1.8 g). Yield 75% (ESI 335.2(M+H) + ).
  • Step 2 ethyl 2-(5-allyl-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-3- cyclopropylpropanoate
  • ethyl 2-(5-bromo-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-3- cyclopropylpropanoate 2.3 g, 6.02 mmol
  • allyltributylstannane 2.4 g, 7.22 mmol
  • Pd 2 dba 3 348 mg, 0.30 mmol
  • tricyclohexyl phosphine 168 mg, 0.60 mmol
  • CsF 1.8 g, 12.04 mmol
  • Step 3 ethyl 3-cyclopropyl-2-(2-oxo-5-(2-oxoethyl)-4-(trifluoromethyl)pyridin-1(2H)- yl)propanoate
  • ethyl 2-(5-allyl-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-3- cyclopropylpropanoate 1.5 g, 4.37 mmol
  • THF/H 2 O 20 mL/20 mL
  • K 2 OsO 4 -2H 2 O (16.0 mg, 0.0437 mmol) in H 2 O (3 mL) and stirred at room temperature for 1 hour.
  • Step 4 ethyl 3-cyclopropyl-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)propanoate
  • DCE dimethylamine hydrochloride
  • Step 5 3-cyclopropyl-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- 1(2H)-yl)propanoic acid
  • Ethyl 3-cyclopropyl-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)- yl)propanoate 400 mg, 1.07 mmol
  • LiOH-H 2 O 224 mg, 5.35 mmol
  • EtOH 5 mL
  • water 2 mL
  • the mixture was acidified with 1N HCl to pH 5 ⁇ 6 and purified by reverse phase HPLC on a C18/120 g column (A: water/10 mM NH 4 HCO 3, B: MeOH, 0 ⁇ 100%) to provide 3-cyclopropyl-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)- yl)propanoic acid as a white solid (150 mg). Yield 41% (ESI 347.0 (M+H) + ).
  • Step 2 (E)-ethyl 2-(5-(2-ethoxyvinyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-5- methylhexanoate A mixture of ethyl 2-(5-bromo-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-5- methylhexanoate (5.56 g, 13.97 mmol), (E)-1-ethoxyethene-2-boronic acid pinacol ester (4.15 g, 20.95 mmol), tetrakis(triphenylphosphine)palladium(0) (2.42 g, 2.10 mmol) and K 2 CO 3 (5.79 g, 41.91 mmol) in co-solvent of anhydrous 1,4-dioxane (140 mL) and water (14 mL) was heated at 70 °C under nitrogen atmosphere for 20 h.
  • Step 3 ethyl 5-methyl-2-(2-oxo-5-(2-oxoethyl)-4-(trifluoromethyl)pyridin-1(2H)- yl)hexanoate
  • Trifluoroacetic acid 32 mL, 430.80 mmol
  • (E)-ethyl 2-(5- (2-ethoxyvinyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-5-methylhexanoate 5.2 g, 13.35 mmol
  • DCM 64 mL
  • Step 4 ethyl 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)- 5-methylhexanoate
  • ethyl 5-methyl-2-(2-oxo-5-(2-oxoethyl)-4-(trifluoromethyl)pyridin-1(2H)- yl)hexanoate 1.6 g, 4.45 mmol
  • dimethylamine 60 mL, 2M in THF, 120 mmol
  • 1,2- dichloroethane 43 mL
  • Step 5 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-5- methylhexanoic acid
  • the reaction mixture was acidified to pH 4 ⁇ 5 with 1N HCl.
  • Step 3 ethyl (3R)-2-(5-allyl-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-3- methylpentanoate
  • ethyl (3R)-2-(5-bromo-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-3- methylpentanoate 2.2 g, 5.74 mmol
  • allyltributylstannane (2.28 g, 6.89 mmol)
  • Pd(PPh3)4 0.67 g, 0.58 mmol
  • the reaction mixture was concentrated in vacuo. The residue was diluted with 50 mL of EtOAc, poured into 20% aq. KF (100 mL), stirred at 20 ⁇ for 1 hour and then filtered and washed with 100 mL of EtOAc. The filtrate was extracted with EA (100 mL x 3).
  • Step 4 ethyl (3R)-3-methyl-2-(2-oxo-5-(2-oxoethyl)-4-(trifluoromethyl)pyridin-1(2H)- yl)pentanoate
  • ethyl (3R)-2-(5-allyl-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-3- methylpentanoate (1.51 g, 4.36 mmol) in THF (15 mL) and H 2 O (10 mL) at 0 °C was added K 2 OsO 4 -2H 2 O (130 mg, 0.345 mmol) and stirred at 0 °C for 5 mins.
  • Step 5 ethyl (3R)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- 1(2H)-yl)-3-methylpentanoate
  • DCE dimethylamine hydrochloride
  • Step 6 (3R)-2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)- 3-methylpentanoic acid
  • Step 2 ethyl (E)-2-(5-(2-ethoxyvinyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)- yl)pentanoate
  • Pd(PPh 3 ) 4 (206 mg, 0.17 mmol) and K 2 CO 3 (1.64 g, 11.92 mmol) in 1,4-dioxane (30 mL) and water (3 mL) was stirred at 70 ⁇ under N 2 for 20 h.
  • Step 3 ethyl 2-(2-oxo-5-(2-oxoethyl)-4-(trifluoromethyl)pyridin-1(2H)-yl)pentanoate
  • DCM dimethyl sulfoxide
  • TFA trifluoromethyl sulfoxide
  • Step 4 ethyl 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)- yl)pentanoate
  • DCE dimethylamine
  • Step 5 2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)- yl)pentanoic acid
  • the mixture was purified by reverse phase HPLC on a C18/40 g column (A: water 10 mM NH 4 HCO 3, B: MeOH, 0 ⁇ 100%) to provide 2-(5-(2- (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)pentanoic acid as a yellow oil (430 mg). Yield 73% (ESI 335.1 (M+H) + ).
  • Step 2 ethyl 4-methyl-2-(2-oxo-5-(2-oxoethyl)-4-(trifluoromethyl)pyridin-1(2H)- yl)pentanoate
  • (E)-ethyl 2-(5-(2-ethoxyvinyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4- methylpentanoate 9 g, 24 mmol) in TFA (25 mL) and DCM (25 mL) was stirred at room temperature for 16 h.
  • Step 3 ethyl 2-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin- 1(2H)-yl)-4-methylpentanoate
  • ethyl 4-methyl-2-(2-oxo-5-(2-oxoethyl)-4-(trifluoromethyl)pyridin-1(2H)- yl)pentanoate 10 g crude, 24 mmol
  • DCE 100 mL
  • 3-methoxyazetidine hydrochloride 5.9 g, 48 mmol
  • Step 4 2-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)- yl)-4-methylpentanoic acid
  • Ethyl 2-(5-(2-(3-methoxyazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4- methylpentanoate (8 g, 19 mmol) was treated with LiOH-H 2 O (2.4 g, 57 mmol) in EtOH (60 mL) and water (12 mL) at room temperature for 2 h.
  • reaction mixture was neutralized by 2 N HCl and concentrated in vacuo.
  • residue was purified by reverse phase HPLC on a C18/120 g column (A: water 10 mM NH 4 HCO 3 , B: MeOH, 0 ⁇ 100%) to provide 2-(5-(2-(3- methoxyazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanoic acid as a yellow solid (6 g). Yield 80% (ESI 391.1(M+H) + ).
  • Step 2 ethyl 2-(5-allyl-3-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentanoate
  • ethyl 2-(5-bromo-3-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentanoate 2.5 g, 7.57 mmol
  • allyltributylstannane 2.5 g, 7.57 mmol
  • dioxane 25 mL
  • Pd 2 (dba) 3 0.3 g, 0.38 mmol
  • CsF 2.3 g,15.1 mmol
  • tricyclohexyl phosphine 212.0 mg, 0.76 mmol
  • Step 3 ethyl 4-methyl-2-(3-methyl-2-oxo-5-(2-oxoethyl)pyridin-1(2H)-yl)pentanoate
  • ethyl 2-(5-allyl-3-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (1.61 g, 5.53 mmol) in THF/H 2 O (24 mL/12 mL) was added a solution of K 2 OsO 4 -2H 2 O (21 mg, 0.058 mmol) in H 2 O (4 mL) and stirred at room temperature for 1 h.
  • Step 4 ethyl 2-(5-(2-(dimethylamino)ethyl)-3-methyl-2-oxopyridin-1(2H)-yl)-4- methylpentanoate
  • ethyl 4-methyl-2-(3-methyl-2-oxo-5-(2-oxoethyl)pyridin-1(2H)-yl)pentanoate (2 g, 16.2 mmol)
  • dimethylamine (2M in THF) (41 mL) in DCE (10 mL) was stirred at room temperature for 30 mins.
  • NaBH(OAc) 3 5.2 g, 24.39 mmol
  • reaction mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC on a C18/40 g column (A: water 10 mM NH 4 HCO 3, B: MeOH, 0 ⁇ 100%) to provide ethyl 2-(5-(2-(dimethylamino)ethyl)-3-methyl-2-oxopyridin- 1(2H)-yl)-4-methylpentanoate as a yellow oil (1 g). Yield 46% (ESI 323.2 (M+H) + ).
  • Step 5 2-(5-(2-(dimethylamino)ethyl)-3-methyl-2-oxopyridin-1(2H)-yl)-4- methylpentanoic acid
  • Step 2 5-bromo-3-(difluoromethyl)pyridin-2-ol
  • a mixture of 5-bromo-3-(difluoromethyl)-2-methoxypyridine (11.0 g, 46.2 mmol) in HBr (33% in acetic acid, 100 mL) was stirred at room temperature for 5 hours and then at 40°C for 75 mins.
  • the mixture was concentrated and poured into 100 mL of saturated NaHCO 3 solution and extracted with DCM.
  • the combined organic layers dried over Na2SO4 and concentrated in vacuo to give 5-bromo-3-(difluoromethyl)pyridin-2-ol as a white solid (8.5 g) used without further purification.
  • Step 3 ethyl 2-(5-bromo-3-(difluoromethyl)-2-oxopyridin-1(2H)-yl)-4
  • a mixture of 5-bromo-3-(difluoromethyl)pyridin-2-ol (7.0 g, 31.2 mmol), ethyl 4-methyl-2- ((methylsulfonyl)oxy)pentanoate (14.0 g, 37.4 mmol) and K2CO3 (14.0 g, 62.5 mmol) in ACN (100 mL) was stirred at 80°C overnight. The mixture was filtered and washed with ACN (20 mL).
  • Step 4 ethyl 2-(5-allyl-3-(difluoromethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoate
  • Step 5 ethyl 2-(3-(difluoromethyl)-2-oxo-5-(2-oxoethyl)pyridin-1(2H)-yl)-4- methylpentanoate
  • ethyl 2-(5-allyl-3-(difluoromethyl)-2-oxopyridin-1(2H)-yl)-4 3.0 g, 9.1 mmol
  • THF/H 2 O 2/1, 100 mL
  • K2OsO4 33.7 mg, 0.09 mmol
  • Step 6 ethyl 2-(3-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)- 4-methylpentanoate
  • ethyl 2-(3-(difluoromethyl)-2-oxo-5-(2-oxoethyl)pyridin-1(2H)-yl)-4- methylpentanoate (3.0 g, 9.1 mmol), dimethylamine (2M in THF, 14 mL, 28 mmol) in DCE (50 mL) was stirred at room temperature for 30 mins.
  • Step 7 2-(3-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4- methylpentanoic acid
  • Step 2 ethyl 2-(5-allyl-3-fluoro-2-oxopyridin-1(2H)-yl)-4-methylpentanoate
  • ethyl 2-(5-bromo-3-fluoro-2-oxopyridin-1(2H)-yl)-4-methylpentanoate 5.0 g, 7.6 mmol
  • allyltributylstannane 6.0 g, 9.1 mmol
  • Pd 2 dba 3 240.0 mg, 0.76 mmol
  • tricyclohexyl phosphine 450 mg, 0.76 mmo
  • CsF 46 g, 15.1 mmol
  • Step 3 ethyl 2-(3-fluoro-2-oxo-5-(2-oxoethyl)pyridin-1(2H)-yl)-4-methylpentanoate
  • ethyl 2-(5-allyl-3-fluoro-4-methyl-2-oxopyridin-1(2H)-yl)-4- methylpentanoate 5.5 g, 18.6 mmol
  • THF/H 2 O 60 mL/20 mL
  • K2OsO4-2H 2 O 60.0 mg, 0.16 mmol
  • Step 4 ethyl 2-(5-(2-(dimethylamino)ethyl)-3-fluoro-2-oxopyridin-1(2H)-yl)-4- methylpentanoate
  • DCE dimethylamine
  • Step 5 2-(5-(2-(dimethylamino)ethyl)-3-fluoro-2-oxopyridin-1(2H)-yl)-4- methylpentanoic acid
  • Ethyl 2-(5-(2-(dimethylamino)ethyl)-3-fluoro-2-oxopyridin-1(2H)-yl)-4-methylpentanoate (800 mg, 2.45 mmol) was treated with LiOH-H 2 O (310.0 mg, 7.35 mmol) in THF (4 mL) and water (1 mL) at room temperature for 2 hours. The THF was removed and the aqueous acidified with 1N HCl to pH 5 ⁇ 6.
  • Step 2 2-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4- methylpentanoic acid Methyl ethyl 2-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4- methylpentanoate (86 mg, 0.24 mmol) was treated with LiOH monohydrate (50 mg, 1.2 mmol) in THF (3 mL) and H 2 O (0.5 mL) at room temperature for 1 hour.
  • LiOH monohydrate 50 mg, 1.2 mmol
  • H 2 O 0.5 mL
  • the reaction mixture was acidified to pH 4 ⁇ 5 with 1N HCl.
  • the residue was purified by reverse phase HPLC on a C18/120 g column (A: water 10 mM NH4HCO3, B: MeOH, 0 ⁇ 100%) to provide 2-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4-methylpentanoic acid as a white solid (55 mg). Yield 70% (ESI 329.1 (M+H) + ).
  • Step 2 ethyl 2-(5-allyl-3-fluoro-2-oxopyridin-1(2H)-yl)pentanoate
  • ethyl 2-(5-bromo-3-fluoro-2-oxopyridin-1(2H)-yl)pentanoate 2.9 g, 13.2 mmol
  • 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.66 g, 15.8 mmol
  • Pd(dppf)Cl2 482.5 mg, 0.66 mmol
  • K3PO4 5.60 g, 26.4 mmol
  • reaction mixture was diluted with 50 mL of water, extracted with EA (60 mL x 2). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo and the residue purified by silica gel column (pet ether: EtOAc 1:2) to provide ethyl 2-(5-allyl-3-fluoro-2- oxopyridin-1(2H)-yl)pentanoate as a white oil (1.9 g). Yield 75% (ESI 282.24(M+H) + ).
  • Step 3 ethyl 2-(3-fluoro-2-oxo-5-(2-oxoethyl)pyridin-1(2H)-yl)pentanoate
  • ethyl ethyl 2-(5-allyl-3-fluoro-2-oxopyridin-1(2H)-yl)pentanoate 1.9 g, 6.7 mmol
  • H 2 O 30 mL
  • K 2 OsO 4 25.8 mg, 0.07 mmol
  • NaIO4 (3.9, 13.4 mmol) was added and the mixture was stirred at room temperature for 2 hours.
  • Step 4 ethyl 2-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)- yl)pentanoate
  • ethyl 2-(3-fluoro-2-oxo-5-(2-oxoethyl)pyridin-1(2H)-yl)pentanoate 1.7 g, 6 mmol
  • AcOH (0.44 g, 7.2 mmol
  • 3-fluoroazetidine hydrochloride 1.0 g, 9.0 mmol
  • Step 5 2-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)pentanoic acid
  • Ethyl 2-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)pentanoate 700 mg, 2.05 mmol
  • LiOH-H 2 O 344 mg, 8.2 mmol
  • EtOH 4 mL
  • H 2 O (1 mL
  • reaction mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC on a C18/40 g column (A: water 10 mM NH4HCO3, B: MeOH, 20%) to provide 2-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)pentanoic acid as a yellow solid (500 mg). Yield 78% (ESI 315.14 (M+H) + ).
  • Step 2 methyl (3R)-2-bromo-3-methylpentanoate
  • (2R, 3R)-2-bromo-3-methylpentanoic acid (12.6 g, 64.60 mmol) in MeOH/CHCl 3 (30 mL/90 mL) was cooled to 0°C.
  • (Diazomethyl)trimethylsilane 2.0 M in hexane; 64.6 m L, 129.20 mmol
  • Step 3 methyl (3R)-2-(5-bromo-3-fluoro-2-oxopyridin-1(2H)-yl)-3-methylpentanoate
  • a mixture of 5-bromo-3-fluoropyridin-2(1H)-one (3.1 g, 16.15 mmol), Cs 2 CO 3 (10.5 g, 32.3 mmol) and methyl (3R)-2-bromo-3-methylpentanoate (5.06 g, 24.23 mmol) in dioxane (100 mL) was stirred at 110°C for 16 h. LCMS showed the reaction was completed. The mixture was filtered and washed with EtOAc (20 mL).
  • Step 4 methyl (3R)-2-(5-allyl-3-fluoro-2-oxopyridin-1(2H)-yl)-3-methylpentanoate
  • methyl (3R)-2-(5-bromo-3-fluoro-2-oxopyridin-1(2H)-yl)-3-methylpentanoate 2.2 g, 6.87 mmol
  • 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 3.5 g, 20.61 mmol
  • Pd(dppf)Cl 2 (251 mg, 0.34 mmol)
  • K 3 PO 4 2.9 g, 13.74 mmol, 2.0 eq
  • Step 5 methyl (3R)-2-(3-fluoro-2-oxo-5-(2-oxoethyl)pyridin-1(2H)-yl)-3- methylpentanoate
  • a solution of methyl (3R)-2-(5-allyl-3-fluoro-2-oxopyridin-1(2H)-yl)-3-methylpentanoate 1.2 g, 4.27 mmol
  • THF/H 2 O 20 mL/20 mL
  • K2OsO4-2H 2 O (15.7 mg, 0.043 mmol) in H 2 O (3 mL) and stirred at room temperature for 1 hour.
  • Step 6 methyl (3R)-2-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)- yl)-3-methylpentanoate
  • 3-fluoroazetidine hydrochloride 768 mg, 6.89 mmol
  • Step 7 (3R)-2-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-3- methylpentanoic acid
  • Methyl (3R)-2-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-3- methylpentanoate (800 mg, 2.34 mmol) was treated with LiOH-H 2 O (491 mg, 11.7 mmol) in EtOH (5 mL) and water (2 mL) and the mixture was stirred at room temperature for 30 minutes.
  • Step 2 ethyl 2-(5-allyl-3-fluoro-2-oxopyridin-1(2H)-yl)-3-cyclopropylpropanoate
  • ethyl 2-(5-bromo-3-fluoro-2-oxopyridin-1(2H)-yl)-3-cyclopropylpropanoate 1.5 g, 4.5 mmol
  • allyltributylstannane 1.5 g, 5.4 mmol
  • CsF 1.4 g, 9 mmol
  • Pd(dba)3 126 mg, 0.45 mmol
  • PCy 3 206 mg, 0.225 mmol
  • Step 3 ethyl 3-cyclopropyl-2-(3-fluoro-2-oxo-5-(2-oxoethyl)pyridin-1(2H)-yl)propanoate
  • ethyl 2-(5-allyl-3-fluoro-2-oxopyridin-1(2H)-yl)-3-cyclopropylpropanoate 800 mg, 2.7 mmol
  • THF/H 2 O 60 mL/20 mL
  • K 2 OsO 4 -2H 2 O 10 mg, 0.027 mmol
  • Step 4 ethyl 3-cyclopropyl-2-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin- 1(2H)-yl)propanoate
  • a mixture of ethyl 3-cyclopropyl-2-(3-fluoro-2-oxo-5-(2-oxoethyl)pyridin-1(2H)- yl)propanoate 500 mg, 1.7 mmol
  • 3-fluoroazetidine hydrochloride 188 mg, 1.7 mmol
  • the reaction mixture was acidified to pH 5 with 1N HCl and concentrated.
  • the mixture was purified by reverse phase HPLC on a C18 / 40 g column (A: water, B: MeOH, 0 ⁇ 100%) to provide 2-(3-fluoro-5-(2-(3- fluoroazetidin-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentanoic acid as a white solid (200 mg). Yield 86% (ESI 327 (M+H) + ).
  • Step 2 ethyl 2-(5-allyl-3-fluoro-2-oxopyridin-1(2H)-yl)-3-methylbutanoate
  • Step 3 ethyl 2-(3-fluoro-2-oxo-5-(2-oxoethyl)pyridin-1(2H)-yl)-3-methylbutanoate
  • ethyl 2-(5-allyl-3-fluoro-2-oxopyridin-1(2H)-yl)-3-methylbutanoate 2.4 g, 8.6 mmol, 1.0 eq
  • H 2 O H 2 O
  • K 2 OsO 4 -2H 2 O 32 mg, 0.086 mmol, 0.01 eq
  • Step 4 ethyl 2-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-3- methylbutanoate
  • ethyl 2-(3-fluoro-2-oxo-5-(2-oxoethyl)pyridin-1(2H)-yl)-3-methylbutanoate 1.6 g, 5.7 mmol, 1.0 eq
  • 3-fluoroazetidine hydrochloride 427.5 mg, 5.7 mmol, 1.0 eq
  • Step 5 2-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-3- methylbutanoic acid
  • the reaction mixture was acidified to pH 5 with 1N HCl and concentrated.
  • the mixture was purified by reverse phase HPLC on a C18 / 40 g column (A: water 10 mM NH 4 HCO 3, B: MeOH, 0 ⁇ 100%) to provide 2-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-3- methylbutanoic acid as a white solid (500 mg). Yield 78% (ESI 315.1 (M+H) + ).
  • Step 2 2-(3-fluoro-5-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4- methylpentanoic acid
  • Ethyl 2-(3-fluoro-5-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-2-oxopyridin-1(2H)-yl)-4- methylpentanoate (1.7 g, 4.59 mmol) was treated with LiOH-H 2 O (960.0 mg, 23.0 mmol, 5.0 eq) in MeOH (12 mL) and water (5 mL) at room temperature for 2 hours.
  • Step 2 5-bromo-3-fluoro-4-methylpyridin-2(1H)-one To a solution of 3-fluoro-4-methylpyridin-2(1H)-one (2.4 g, 18.9 mmol, 1.0 eq) in DMF (20 mL) was added NBS (3.7 g, 20.8 mmol, 1.1 eq) and stirred at 30°C for 1 h.
  • reaction mixture was purified by reverse phase HPLC (A: water(0.01%TFA); B ACN, 45% of B) to provide 5-bromo-3-fluoro-4-methylpyridin-2(1H)-one as a whitle solid (3 g). Yield 77% (ESI 206 (M+H) + ).
  • Step 3 ethyl 2-(5-bromo-3-fluoro-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentanoate
  • Step 4 ethyl 2-(5-allyl-3-fluoro-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentanoate
  • ethyl 2-(5-bromo-3-fluoro-4-methyl-2-oxopyridin-1(2H)-yl)-4- methylpentanoate (4.5 g, 13 mmol, 1.0 eq), allyltributylstannane (35.6 g, 16.9 mmol, 1.3 eq), Pd 2 dba 3 (595 mg, 0.65 mmol, 0.05 eq), tricyclohexyl phosphine (364 mg, 1.3 mmol, 0.1 eq) and CsF (4 g, 26 mmol, 2.0 eq) in anhydrous dioxane (100 mL) was stirred under N2 at 100°C for 16 hours.
  • Step 5 ethyl 2-(3-fluoro-4-methyl-2-oxo-5-(2-oxoethyl)pyridin-1(2H)-yl)-4- methylpentanoate
  • ethyl 2-(5-allyl-3-fluoro-4-methyl-2-oxopyridin-1(2H)-yl)-4- methylpentanoate 1.8 g, 5.8 mmol, 1.0 eq
  • THF/H 2 O 60 mL/20 mL
  • K2OsO4-2H 2 O 21 mg, 0.058 mmol, 0.01 eq
  • Step 6 ethyl 2-(5-(2-(dimethylamino)ethyl)-3-fluoro-4-methyl-2-oxopyridin-1(2H)-yl)-4- methylpentanoate
  • ethyl 2-(3-fluoro-4-methyl-2-oxo-5-(2-oxoethyl)pyridin-1(2H)-yl)-4- methylpentanoate 2.0 g, 6.42 mmol
  • dimethylamine (9.64 mL, 19.27 mmol) (2.0 M) in THF was added in DCE (32.1 mL) and stirred at room temperature for 10 mins.
  • Step 7 2-(5-(2-(dimethylamino)ethyl)-3-fluoro-4-methyl-2-oxopyridin-1(2H)-yl)-4- methylpentanoic acid
  • Step 2 2-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4- methylpentanoic acid
  • Ethyl 2-(3-fluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4- methylpentanoate (1 g, 2.7 mmol, 1.0 eq) was treated with LiOH-H 2 O (567 mg, 13.5 mmol, 5.0 eq) in MeOH (10 mL) and water (5 mL) at room temperature for 2 hours.
  • the reaction mixture was acidified to pH 5 with 1N HCl and concentrated.
  • the mixture was purified by reverse phase HPLC in neutral condition (A: water, B: MeOH, 60%B) to provide 2-(3-fluoro- 5-(2-(3-fluoroazetidin-1-yl)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentanoic acid as a white solid (800 mg). Yield 86% (ESI 343 (M+H) + ).
  • Step 2 ethyl 2-(5-bromo-3-fluoro-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4- methylpentanoate
  • a mixture of 5-bromo-3-fluoro-4-(trifluoromethyl)pyridin-2-ol (19.7 g, 75.77 mmol), Cs2CO3 (49.3 g, 151.54 mmol) and ethyl 4-methyl-2-((methylsulfonyl)oxy)pentanoate (23.5 g, 98.5 mmol) in toluene (100 mL) was stirred at 110°C for 2 h. LCMS showed the reaction was completed.
  • Step 3 ethyl (E)-2-(5-(2-ethoxyvinyl)-3-fluoro-2-oxo-4-(trifluoromethyl)pyridin-1(2H)- yl)- 4-methylpentanoate
  • E 2-(5-bromo-3-fluoro-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4- methylpentanoate (9.7 g, 24.12 mmol)
  • Pd(PPh 3 ) 4 (832 mg, 0.72 mmol,) and K 2 CO 3 (6.7 g, 48.24 mmol) in 1,4-dioxane (100 mL) and water (10 mL) was stirred at 70 ⁇ under N 2 for 20 h.
  • Step 4 ethyl 2-(3-fluoro-2-oxo-5-(2-oxoethyl)-4-(trifluoromethyl)pyridin-1(2H)-yl)-4- methylpentanoate
  • ethyl (E)-2-(5-(2-ethoxyvinyl)-3-fluoro-2-oxo-4-(trifluoromethyl)pyridin- 1(2H)-yl)-4-methylpentanoate 6.0 g, 15.25 mmol
  • TFA 5 mL
  • Step 5 ethyl 2-(5-(2-(dimethylamino)ethyl)-3-fluoro-2-oxo-4-(trifluoromethyl)pyridin- 1(2H)-yl)-4-methylpentanoate
  • DCE dimethylamine hydrochloride
  • Step 6 2-(5-(2-(dimethylamino)ethyl)-3-fluoro-2-oxo-4-(trifluoromethyl)pyridin-1(2H)- yl)-4-methylpentanoic acid
  • Example 3 Synthesis of examplary compounds of the invention Prep-HPLC Methods Crude samples were dissolved in MeOH and purified by prep HPLC using a Gilson 215 instrument, detection wavelength 214 nm: Prep HPLC A: column: Xtimate C18, 21.2 * 250 mm, 10 ⁇ m; mobile phase: A water (10 mM ammonium hydrogen carbonate), B CH3CN; gradient elution as in text; flow rate: 30 mL/min. Prep HPLC B: column: Xtimate C18, 21.2 * 250 mm, 10 ⁇ m; mobile phase: A water (0.1% formic acid), B CH3CN; gradient elution as in text; flow rate: 30 mL/min. 3-1.
  • reaction mixture was poured into 100 mL of EtOAc, washed with water (30 mL), brine (30 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • the reaction mixture was concentrated in vacuo and purified by reverse phase HPLC on a C18/40 g column (A: water/0.01%TFA, B: MeOH, 0 ⁇ 64%) to provide (3S)-ethyl 3-(4,5-difluoro-2',6'- dimethylbiphenyl-3-yl)-3-(2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-4-methyl-2-oxopyridin- 1(2H)-yl)-4-methylpentanamido)propanoate as a white solid (131 mg).
  • reaction mixture was acidified to pH 4 ⁇ 5 with concentrated HCl.
  • the reaction mixture was concentrated in vacuo and purified by prep- HPLC A (30-60% MeCN) to give the diastereomeric products D-P1 (23 mg) and D-P2 (23 mg) as a white solid.
  • reaction mixture was concentrated in vacuo and purified by reverse phase HPLC on a C18 / 40 g column (A: water 10 mM NH4HCO3, B: MeOH, 0 ⁇ 100%) to provide ethyl (3S)-3-(3-cyclopropyl-2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)- yl)propanamido)-3-(4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoate as a yellow oil (60 mg). Yield 35% (ESI 624.2 (M+H) + ).
  • Step 2 (3S)-3-(3-cyclopropyl-2-(5-(2-(3-fluoroazetidin-1-yl)ethyl)-2-oxopyridin-1(2H)- yl)propanamido)-3-(4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)propanoic acid
  • reaction mixture was acidified to pH 4 ⁇ 5 with 1N HCl.
  • the solvent was removed in vacuo and the residue was purified by prep-HPLC A (30-60% MeCN) to give the diastereomeric products E-P1 (1 mg) and E-P2 (1 mg) as a white solid.
  • Step 2 (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)- yl)-3-methylbutanamido)-3-(4-fluoro-2',4',5,6'-tetramethylbiphenyl-3-yl)propanoic acid (3S)-ethyl 3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-3- methylbutanamido)-3-(4-fluoro-2',4',5,6'-tetramethylbiphenyl-3-yl)propanoate (100 mg, 0.15 mmol) was treated with LiOH-H 2 O (32 mg, 0.75 mmol) in MeOH (3 mL) and H 2 O (1 mL) at room temperature for 3 hours.
  • reaction mixture was acidified to pH 4 ⁇ 5 with 1N HCl.
  • the solvent was removed in vacuo and the residue was purified by prep-HPLC A (30-60% MeCN) to give the diastereomeric products F-P1 (30.0 mg) and F-P2 (32.0 mg) as a white solid.
  • reaction mixture was concentrated in vacuo and purified by reverse phase HPLC on a C18 / 40 g column (A: water 10 mM NH4HCO3, B: MeOH, 0 ⁇ 100%) to provide (3S)-ethyl 3-(2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4- methylpentanamido)-3-(4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoate as colorless oil (155 mg). Yield 51% (ESI 726.1 (M+H) + ).
  • Step 2 (3S)-3-(2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)- 4-methylpentanamido)-3-(4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)biphenyl-3- yl)propanoic acid (3S)-ethyl 3-(2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4- methylpentanamido)-3-(4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoate (155 mg, 0.21 mmol) was treated with LiOH monohydrate (35 mg, 0.84 mmol) in MeOH (4 mL) and H
  • reaction mixture was acidified to pH 4 ⁇ 5 with 1N HCl.
  • the mixture was concentrated in vacuo and the residue was purified by prep-HPLC A (30-65% MeCN) to give the diastereomeric products G-P1 (37.8 mg) and G- P2 (49.6 mg) as a white solid.
  • Step 2 (3S)-3-(2-(3-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)- yl)-4-methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3- yl)propanoic acid
  • Ethyl (3S)-3-(2-(3-(difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4- methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)propanoate (150 mg, 0.23 mmol) was treated with LiOH-H 2 O (95.5mg, 2.3 mmol) in T
  • reaction mixture was acidified to pH 4 ⁇ 5 with 1N HCl.
  • the solvent was removed in vacuo and the residue was purified by prep-HPLC A (30- 70% MeCN) to give the diastereomeric products H-P1 (24.0 mg) and H-P2 (33.0 mg) as a white solid.
  • reaction mixture was concentrated in vacuo and purified by reverse phase HPLC on a C18 / 40 g column (A: water 10 mM NH 4 HCO 3, B: MeOH, 0 ⁇ 100%) to provide ethyl (3S)-3-(4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(3- (difluoromethyl)-5-(2-(dimethylamino)ethyl)-2-oxopyridin-1(2H)-yl)-4- methylpentanamido)propanoate as brown solid (150 mg). Yield 63.2% (ESI 660.3 (M+H) + ).
  • reaction mixture was acidified to pH 4 ⁇ 5 with 1N HCl.
  • the solvent was removed in vacuo and the residue was purified by prep-HPLC A (30- 60% MeCN) to provide the diastereomeric products I-P1 (20 mg) and I-P2 (22 mg) as a white solid.
  • reaction mixture was concentrated in vacuo and purified by reverse phase HPLC on a C18 / 40 g column (A: water 10 mM NH4HCO3, B: MeOH, 0 ⁇ 100%) to provide (3S)-ethyl 3- (2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-5-methylhexanamido)-3- (4-fluoro-2',5,6'-trimethylbiphenyl-3-yl)propanoate as colorless oil (170 mg). Yield 56% (ESI 620.2 (M+H) + ).
  • Step 2 (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-5- methylhexanamido)-3-(4-fluoro-2',5,6'-trimethylbiphenyl-3-yl)propanoic acid (3S)-ethyl 3-(2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-5- methylhexanamido)-3-(4-fluoro-2',5,6'-trimethylbiphenyl-3-yl)propanoate (170 mg, 0.27 mmol) was treated with LiOH monohydrate (57 mg, 1.35 mmol) in MeOH (4 mL) and H 2 O (1 mL) at room temperature for 2 hours.
  • reaction mixture was acidified to pH 4 ⁇ 5 with 1N HCl.
  • the reaction mixture was concentrated in vacuo and purified by prep-HPLC A (30- 60% MeCN) to provide the diastereomeric products J-P1 (50 mg) and J-P2 (60.4 mg) as a white solid.
  • reaction mixture was concentrated in vacuo and purified by reverse phase HPLC on a C18 / 40 g column (A: water 10 mM NH 4 HCO 3, B: MeOH, 0 ⁇ 100%) to provide (3S)-ethyl 3-(2-(5-(2-(dimethylamino)ethyl)-3-fluoro-2-oxopyridin-1(2H)-yl)-4- methylpentanamido)-3-(4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoate as yellow oil (150 mg). Yield 51% (ESI 664.2 (M+H) + ).
  • Step 2 (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-3-fluoro-2-oxopyridin-1(2H)-yl)-4- methylpentanamido)-3-(4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)biphenyl-3- yl)propanoic acid (3S)-ethyl 3-(2-(5-(2-(dimethylamino)ethyl)-3-fluoro-2-oxopyridin-1(2H)-yl)-4- methylpentanamido)-3-(4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)biphenyl-3-yl)propanoate (150 mg, 0.23 mmol) was treated with LiOH monohydrate (39 mg, 0.92 mmol) in MeOH (4 mL) and H 2 O (1 mL) at 36°C for 2
  • reaction mixture was acidified to pH 4 ⁇ 5 with 1N HCl.
  • the reaction mixture was concentrated in vacuo and purified by prep-HPLC A (30- 60% MeCN) to give the diastereomeric products K-P1 (41 mg) and K-P2 (46.8 mg) as a white solid.
  • reaction mixture was concentrated in vacuo and purified by reverse phase HPLC on a C18 / 40 g column (A: water 10 mM NH4HCO3, B: MeOH, 0 ⁇ 100%) to provide ethyl (3S)-3-(4,5- difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoate as a yellow solid (131 mg). Yield 68.1% (ESI 664.2 [M+H] + ).
  • Step 2 (3S)-3-(4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(5-(2- (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4- methylpentanamido)propanoic acid
  • Ethyl (3S)-3-(4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(5-(2- (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4- methylpentanamido)propanoate (131.0 mg, 0.19 mmol) was treated with LiOH-H 2 O (100.0 mg, 2.38 mmol) in THF (2 mL) and water (
  • reaction mixture was acidified to pH 4 ⁇ 5 with 2N HCl.
  • the solvent was removed in vacuo and the residue was purified by prep-HPLC A (30-60% MeCN) to give the diastereomeric product L-P1 (11.1 mg) and L-P2 (19.0 mg) as a white solid.
  • reaction mixture was concentrated in vacuo and purified by reverse phase HPLC on a C18 / 40 g column (A: water 10 mM NH4HCO3, B: MeOH, 0 ⁇ 100%) to provide ethyl (3S)-3-(4,4'-difluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)-3-(2-(5-(2- (dimethylamino)ethyl)-3-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)propanoate as a colorless oil (180 mg).
  • reaction mixture was acidified to pH 4 ⁇ 5 with 1N HCl.
  • the solvent was removed in vacuo and the residue was purified by prep-HPLC A (30-60% MeCN) to give the diastereomeric products M-P1 (50 mg) and M-P2 (53.0 mg) as a white solid.
  • reaction mixture was concentrated in vacuo and purified by reverse phase HPLC on a C18 / 40 g column (A: water 10 mM NH4HCO3, B: MeOH, 0 ⁇ 100%) to provide ethyl (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-3-fluoro-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)-3-(4-fluoro-4'-methoxy-2',5,6'- trimethyl-[1,1'-biphenyl]-3-yl)propanoate (214 mg) as a white solid.
  • reaction mixture was acidified to pH 4 ⁇ 5 with 1N HCl.
  • the solvent was removed in vacuo and the residue was purified by prep-HPLC A (30-60% CH 3 CN) to give the diastereomeric products P-P1 (39.8 mg) and P-P2 (48.6 mg) as a white solid.
  • Step 2 (3S)-3-(2-(5-(2-(azetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)- 4-methylpentanamido)-3-(4,4'-difluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'- biphenyl]-3-yl)propanoic acid
  • reaction mixture was acidified to pH 4 ⁇ 5 with 1N HCl.
  • the solvent was removed in vacuo and the residue was purified by prep-HPLC A (30-60% MeCN) to give the diastereomeric products R-P1 (65.0 mg) and R-P2 (35.0 mg) as a white solid.
  • reaction mixture was concentrated in vacuo and purified by reverse phase HPLC on a C18 / 40 g column (A: water 10 mM NH4HCO3, B: MeOH, 0 ⁇ 100%) to provide ethyl (S)-3-(4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(5-(2- (dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)propanoate as yellow oil (75 mg). Yield 45% (ESI 610.3 (M+H) + ).
  • Step 2 (S)-3-(4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(5-(2- (dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4- methylpentanamido)propanoic acid Ethyl (S)-3-(4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-((S)-2-(5-(2- (dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4-methylpentanamido)propanoate (75 mg, 0.12 mmol) was treated with LiOH monohydrate (26 mg, 0.62 mmol) in MeOH (2 mL) and H 2 O (1 mL) at room temperature for
  • reaction mixture was acidified to pH 4 ⁇ 5 with 1N HCl.
  • the mixture was concentrated in vacuo and the residue was purified by prep-HPLC A (30-60% MeCN) to give the diastereomeric products S-P1 (28 mg) and S-P2 (38 mg) as a white solid.
  • reaction mixture was concentrated in vacuo and purified by reverse phase HPLC on a C18 / 40 g column (A: water 10 mM NH4HCO3, B: MeOH, 0 ⁇ 100%) to provide ethyl (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4- methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)propanoate as a white oil (95.0 mg). Yield 45% (ESI 620.3 (M+H) + ).
  • Step 2 (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4- methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)propanoic acid
  • Ethyl (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-4-methyl-2-oxopyridin-1(2H)-yl)-4- methylpentanamido)-3-(4-fluoro-2',4',5,6'-tetramethyl-[1,1'-biphenyl]-3-yl)propanoate (95.0 mg, 0.15 mmol) was treated with LiOH-H 2 O (25.2 mg, 0.60 mmol) in MeOH (4 mL) and H 2 O (1 mL) at
  • reaction mixture was acidified to pH 4 ⁇ 5 with 1N HCl.
  • the solvent was removed in vacuo and the residue was purified by prep-HPLC A (30-60% MeCN) to give the diastereomeric products T-P1 (26.2 mg) and T-P2 (58.3 mg) as a white solid.
  • Step 2 (3S)-3-(4-fluoro-3'-methoxy-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(5-(2-(3- methoxyazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4- methylpentanamido)propanoic acid
  • Step 2 (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)- yl)-4-methylpentanamido)-3-(4-fluoro-3'-methoxy-2',5,6'-trimethyl-[1,1'-biphenyl]-3- yl)propanoic acid
  • Ethyl (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4- methylpentanamido)-3-(4-fluoro-3'-methoxy-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate (250 mg, 0.32mmol, 1.00 eq) was treated with LiOH-H 2 O (19 mg, 0.81 mmol
  • reaction mixture was acidified to pH 4 ⁇ 5 with 1N HCl.
  • the solvent was removed in vacuo and the residue was purified by prep-HPLC A (30-60% CH 3 CN) to give the diastereomeric products U-P1 (40.0 mg) and U-P2 (55.0 mg) as a white solid.
  • Step 2 (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)- yl)-4-methylpentanamido)-3-(4-fluoro-4'-methoxy-2',5,6'-trimethyl-[1,1'-biphenyl]-3- yl)propanoic acid
  • Ethyl (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4- methylpentanamido)-3-(4-fluoro-4'-methoxy-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoate (131 mg, 0.19 mmol) was treated with LiOH-H 2 O (32 mg, 0.76 mmol) in MeOH
  • reaction mixture was acidified to pH 4 ⁇ 5 with 1N HCl.
  • the solvent was removed in vacuo and the residue was purified by prep-HPLC A (30-60% CH 3 CN) to give the diastereomeric products V-P1 (24 mg) and V-P2 (15 mg) as a white solid.
  • reaction mixture was concentrated in vacuo and purified by reverse phase HPLC on a C18 / 40 g column (A: water 10 mM NH 4 HCO 3, B: MeOH, 0 ⁇ 100%) to provide ethyl (3S)-3-(5- chloro-4-fluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(5-(2-(3-methoxyazetidin-1- yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4-methylpentanamido)propanoate as a yellow oil (150 mg).
  • Step 2 (3S)-3-(5-chloro-4-fluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(5-(2-(3- methoxyazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4- methylpentanamido)propanoic acid Ethyl (3S)-3-(5-chloro-4-fluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(5-(2-(3- methoxyazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4- methylpentanamido)propanoate (150 mg,
  • reaction mixture was concentrated in vacuo and purified by reverse phase HPLC on a C18 / 40 g column (A: water 10 mM NH 4 HCO 3, B: MeOH, 0 ⁇ 100%) to provide ethyl (3S)-3-(5-chloro-4,4'-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl)-3-(2-(5-(2-(3- methoxyazetidin-1-yl)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-4- methylpentanamido)propanoateas a yellow oil (150 mg).
  • reaction mixture was acidified to pH 4 ⁇ 5 with 1N HCl.
  • the solvent was removed in vacuo and the residue was purified by prep-HPLC A (30-60% CH 3 CN) to give the diastereomeric products X-P1 (35 mg) and X-P2 (49 mg) as a white solid.
  • reaction mixture was concentrated in vacuo and purified by reverse phase HPLC on a C18 / 40 g column (A: water 10 mM NH4HCO3, B: MeOH, 0 ⁇ 80%) to provide (3S)-ethyl 3-(4,4'-difluoro-2',5,6'-trimethylbiphenyl-3-yl)-3-(2-(5-(2- (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-5- methylhexanamido)propanoate as brown solid (262 mg). Yield 97% (ESI 692.3 (M+H) + ).
  • Step 2 (3S)-3-(4,4'-difluoro-2',5,6'-trimethylbiphenyl-3-yl)-3-(2-(5-(2 (dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-5- methylhexanamido)propanoic acid (3S)-ethyl 3-(4,4'-difluoro-2',5,6'-trimethylbiphenyl-3-yl)-3-(2-(5-(2-(dimethylamino)ethyl)- 2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-5-methylhexanamido)propanoate (262 mg, 0.38 mmol) was treated with LiOH monohydrate (80 mg, 1.90 mmol) in EtOH (6 mL) and H 2 O (0.10 mL) at 36°C for 1 hour.
  • reaction mixture was acidified to pH 4 ⁇ 5 with 1N HCl.
  • the reaction mixture was concentrated in vacuo and purified by prep-HPLC A (30-60% MeCN) to give the diastereomeric products Y-P1 (68 mg) and Y-P2 (66 mg) as a white solid.
  • reaction mixture was concentrated in vacuo and purified by reverse phase HPLC on a C18 / 40 g column (A: water 10 mM NH 4 HCO 3, B: MeOH, 0 ⁇ 100%) to provide (3S)-ethyl 3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4- (trifluoromethyl)pyridin-1(2H)-yl)-5-methylhexanamido)-3-(4-fluoro-2',5,6'- trimethylbiphenyl-3-yl)propanoate as a brown solid (223 mg). Yield 71% (ESI 674.3 (M+H) + ).
  • Step 2 (3S)-3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)- yl)-5-methylhexanamido)-3-(4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl)propanoic acid (3S)-ethyl 3-(2-(5-(2-(dimethylamino)ethyl)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-5- methylhexanamido)-3-(4-fluoro-2',5,6'-trimethylbiphenyl-3-yl)propanoate (223 mg, 0.33 mmol) was treated with LiOH monohydrate (35 mg, 0.82 mmol) in EtOH (6 mL) and H 2 O (0.08 mL) at 36 °C for 1
  • the reaction mixture was acidified to pH 4 ⁇ 5 with 1N HCl.
  • the reaction mixture was concentrated in vacuo and purified by prep-HPLC A (30-60% MeCN) to give the diastereomeric products Z-P1 (60 mg) and Z-P2 (59 mg) as a white solid.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Steroid Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Hydrogenated Pyridines (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Radio Relay Systems (AREA)
  • Air Conditioning Control Device (AREA)

Abstract

L'invention concerne des antagonistes à petites molécules de l'intégrine α4β 7 humaine, et des méthodes d'utilisation de ceux-ci pour traiter un certain nombre de maladies et d'états pathologiques.
PCT/US2020/056001 2019-10-16 2020-10-16 INHIBITION DE L'INTÉGRINE α 4 β 7 HUMAINE WO2021076902A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP2022509595A JP7437490B2 (ja) 2019-10-16 2020-10-16 ヒトインテグリン（アルファ－４）（ベータ－７）の阻害
JP2024018765A JP2024054293A (ja) 2019-10-16 2024-02-09 ヒトインテグリン（アルファ－４）（ベータ－７）の阻害

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201962916062P 2019-10-16 2019-10-16
US62/916,062 2019-10-16

Publications (1)

Publication Number Publication Date
WO2021076902A1 true WO2021076902A1 (fr) 2021-04-22

Family

ID=73198501

Family Applications (3)

Application Number Title Priority Date Filing Date
PCT/US2020/056001 WO2021076902A1 (fr) 2019-10-16 2020-10-16 INHIBITION DE L'INTÉGRINE α 4 β 7 HUMAINE
PCT/US2020/055986 WO2021076890A1 (fr) 2019-10-16 2020-10-16 INHIBITION DE L'INTÉGRINE HUMAINE α4β7
PCT/US2021/055196 WO2022081983A1 (fr) 2019-10-16 2021-10-15 Inhibition de l'intégrine humaine a4b7

Family Applications After (2)

Application Number Title Priority Date Filing Date
PCT/US2020/055986 WO2021076890A1 (fr) 2019-10-16 2020-10-16 INHIBITION DE L'INTÉGRINE HUMAINE α4β7
PCT/US2021/055196 WO2022081983A1 (fr) 2019-10-16 2021-10-15 Inhibition de l'intégrine humaine a4b7

Country Status (22)

Country Link
US (3) US20240174632A1 (fr)
EP (2) EP4045039A4 (fr)
JP (6) JP7437495B2 (fr)
KR (2) KR20220102669A (fr)
CN (2) CN115087444A (fr)
AR (1) AR120244A1 (fr)
AU (2) AU2020366435A1 (fr)
BR (1) BR112022007284A2 (fr)
CA (1) CA3154269A1 (fr)
CL (1) CL2022000959A1 (fr)
CO (1) CO2022005759A2 (fr)
CR (1) CR20220205A (fr)
CU (1) CU20220027A7 (fr)
DO (1) DOP2022000081A (fr)
EC (1) ECSP22038978A (fr)
IL (1) IL292296A (fr)
MX (1) MX2022004406A (fr)
PE (1) PE20221829A1 (fr)
TW (4) TWI775182B (fr)
UY (1) UY38926A (fr)
WO (3) WO2021076902A1 (fr)
ZA (1) ZA202203872B (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11104661B1 (en) 2019-10-16 2021-08-31 Morphic Therapeutic, Inc. Inhibiting human integrin (α-4) (β-7)
US11174228B2 (en) 2018-04-12 2021-11-16 Morphic Therapeutic, Inc. Antagonists of human integrin (α4)(β7)
WO2023125182A1 (fr) * 2021-12-27 2023-07-06 海思科医药集团股份有限公司 Dérivé d'acide propionique et son utilisation médicale
US11866429B2 (en) 2019-10-16 2024-01-09 Chemocentryx, Inc. Heteroaryl-biphenyl amines for the treatment of PD-L1 diseases

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114222730A (zh) 2019-08-14 2022-03-22 吉利德科学公司 用于抑制α4β7整合素的化合物
WO2024051819A1 (fr) * 2022-09-09 2024-03-14 西藏海思科制药有限公司 Dérivé d'acide propionique et son utilisation en médecine

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000068188A1 (fr) * 1999-05-07 2000-11-16 Texas Biotechnology Corporation Derives de l'acide propanoique inhibant la liaison des integrines a leurs recepteurs
EP1213288A1 (fr) * 2000-11-06 2002-06-12 Texas Biotechnology Corporation Dérivés de l'acide propanoique qui inhibent la liaison des integrines à leurs récepteurs
WO2019200202A1 (fr) * 2018-04-12 2019-10-17 Morphic Therapeutic, Inc. Antagonistes de l'intégrine humaine (alpha4) (beta7)

Family Cites Families (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU681396B2 (en) 1993-03-31 1997-08-28 G.D. Searle & Co. 1-amidinophenyl-pyrrolidones piperidinones azetinones as platelet aggregation inhibitors
DE4427979A1 (de) 1993-11-15 1996-02-15 Cassella Ag Substituierte 5-Ring-Heterocyclen, ihre Herstellung und ihre Verwendung
US5849736A (en) 1993-11-24 1998-12-15 The Dupont Merck Pharmaceutical Company Isoxazoline and isoxazole fibrinogen receptor antagonists
DE19622489A1 (de) 1996-06-05 1997-12-11 Hoechst Ag Salze des 3-(2-(4-(4-(Amino-imino-methyl)-phenyl)-4- methyl-2,5-dioxo-imidazolidin-1-yl)-acetylamino)-3- phenyl-propionsäure-ethylesters
WO1998016524A1 (fr) 1996-10-11 1998-04-23 Cor Therapeutics, Inc. DERIVES HETEROCYCLIQUES UTILISES COMME INHIBITEURS DE FACTEUR Xa
EP0932615A1 (fr) 1996-10-11 1999-08-04 Cor Therapeutics, Inc. INHIBITEURS SELECTIFS DU FACTEUR Xa
DE19751251A1 (de) 1997-11-19 1999-05-20 Hoechst Marion Roussel De Gmbh Substituierte Imidazolidinderivate, ihre Herstellung, ihre Verwendung und sie enthaltende pharmezeutische Präparate
DE69824037T2 (de) 1997-11-24 2005-06-02 Merck & Co., Inc. Beta-alanin-derivate als zell-adhäsions-inhibitoren
US6645939B1 (en) 1997-11-24 2003-11-11 Merck & Co., Inc. Substituted β-alanine derivatives as cell adhesion inhibitors
MY153569A (en) 1998-01-20 2015-02-27 Mitsubishi Tanabe Pharma Corp Inhibitors of ?4 mediated cell adhesion
DE19821483A1 (de) 1998-05-14 1999-11-18 Hoechst Marion Roussel De Gmbh Imidazolidinderivate, ihre Herstellung, ihre Verwendung und sie enthaltende pharmazeutische Präparate
CA2333647A1 (fr) 1998-06-29 2000-01-06 Dupont Pharmaceuticals Company Isoxazolidines et carbamates cycliques utilises comme antagonistes de iib/iiia
WO2000006169A1 (fr) * 1998-07-29 2000-02-10 Merck & Co., Inc. Antagonistes des recepteurs de l'integrine
GB9826174D0 (en) * 1998-11-30 1999-01-20 Celltech Therapeutics Ltd Chemical compounds
US6972296B2 (en) 1999-05-07 2005-12-06 Encysive Pharmaceuticals Inc. Carboxylic acid derivatives that inhibit the binding of integrins to their receptors
JP2003509488A (ja) 1999-09-24 2003-03-11 ジェネンテック・インコーポレーテッド チロシン誘導体
DE10041423A1 (de) 2000-08-23 2002-03-07 Merck Patent Gmbh Biphenylderivate
BR0113671A (pt) * 2000-08-30 2004-01-06 Pharmacia Corp Antagonistas de integrina alfa v beta 3 gem-substituìda
DE10111876A1 (de) 2001-03-10 2002-09-19 Aventis Pharma Gmbh Bis(trifluormethyl)hydantoine als Zwischenprodukte für pharmazeutische Wirkstoffe
DE10154280A1 (de) 2001-11-05 2003-05-15 Wilex Ag Antagonisten für alpha¶4¶-Integrine
PT1485127E (pt) 2002-02-25 2011-09-07 Elan Pharm Inc Administração de agentes para o tratamento de inflamação
ES2555355T3 (es) 2004-09-03 2015-12-30 Genentech, Inc. Antagonistas anti-beta7 humanizados y utilizaciones para los mismos
US7972775B2 (en) 2005-03-03 2011-07-05 Seedlings Life Science Ventures, Llc Method of risk management for patients undergoing Natalizumab treatment
WO2006126529A1 (fr) 2005-05-25 2006-11-30 Shionogi & Co., Ltd. Derive de morphinane substitue en position 7 par un carbamoyle et insature en positions 6 et 7
AR054129A1 (es) 2005-06-09 2007-06-06 Uc S A Derivados de 2, 6-quinolinilo, una preparacion farmaceutica que los contiene y su empleo en la fabricacion de medicamentos para el tratamiento de enfermedades dependientes de integrinas alfa4beta1 y/o alfa4beta7
JP2009528359A (ja) 2006-02-28 2009-08-06 エラン ファーマシューティカルズ，インコーポレイテッド ナタリズマブを用いて炎症性疾患および自己免疫性疾患を治療する方法
WO2010091411A1 (fr) 2009-02-09 2010-08-12 Glaxosmithkline Llc Agents antiviraux à base de pipéridinyle amido cyclique
AU2012236304C1 (en) 2011-03-31 2017-01-05 Genentech, Inc. Methods of administering beta7 integrin antagonists
BR112015007528A2 (pt) 2012-10-05 2018-09-04 Genentech Inc método para prever a resposta, para prever a responsividade, para identificar e para tratar um paciente que tem uma disfunção inflamatória gastrointestinal.
AR099856A1 (es) 2014-03-27 2016-08-24 Genentech Inc Métodos para diagnosticar y tratar la enfermedad de intestino inflamado
CN105658641B (zh) 2014-07-25 2018-04-17 江苏恒瑞医药股份有限公司 氮茚‑酰胺类衍生物、其制备方法及其在医药上的应用
EP3978530A1 (fr) 2015-02-26 2022-04-06 F. Hoffmann-La Roche AG Antagonistes d'intégrine bêta7 et procédés de traitement de la maladie de crohn
RU2769702C2 (ru) * 2017-02-28 2022-04-05 Морфик Терапьютик, Инк. Ингибиторы интегрина avb6
US10875875B2 (en) * 2017-04-26 2020-12-29 Aviara Pharmaceuticals, Inc. Propionic acid derivatives and methods of use thereof
US10246451B2 (en) 2017-04-26 2019-04-02 Aviara Pharmaceuticals, Inc. Propionic acid derivatives and methods of use thereof
AU2019373242B2 (en) 2018-10-30 2023-07-13 Gilead Sciences, Inc. Compounds for inhibition of alpha 4 beta 7 integrin
KR102641718B1 (ko) 2018-10-30 2024-02-29 길리애드 사이언시즈, 인코포레이티드 알파4베타7 인테그린 억제제로서의 이미다조피리딘 유도체
CA3115830C (fr) * 2018-10-30 2023-09-12 Gilead Sciences, Inc. Composes pour inhibition de l'integrine .alpha.4.beta.7
CN112969687A (zh) 2018-10-30 2021-06-15 吉利德科学公司 作为α4β7整合素抑制剂的喹啉衍生物
UY38926A (es) 2019-10-16 2021-05-31 Morphic Therapeutic Inc INHIBICIÓN DE INTEGRINA alfa4beta7 HUMANA

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000068188A1 (fr) * 1999-05-07 2000-11-16 Texas Biotechnology Corporation Derives de l'acide propanoique inhibant la liaison des integrines a leurs recepteurs
EP1213288A1 (fr) * 2000-11-06 2002-06-12 Texas Biotechnology Corporation Dérivés de l'acide propanoique qui inhibent la liaison des integrines à leurs récepteurs
WO2019200202A1 (fr) * 2018-04-12 2019-10-17 Morphic Therapeutic, Inc. Antagonistes de l'intégrine humaine (alpha4) (beta7)

Non-Patent Citations (12)

* Cited by examiner, † Cited by third party
Title
"Enantioselective Synthesis of p-Amino Acids", 27 January 2005, JOHN WILEY & SONS, INC.
"Handbook of Chemistry and Physics", 1986, pages: 87
A. EL-FAHAMF. ALBERICIO: "Peptide Coupling Reagents, More than a Letter Soup", CHEM. REV., vol. 111, no. 11, 2011, pages 6557 - 6602, XP055708830, DOI: 10.1021/cr100048w
BERGE ET AL.: "Pharmaceutical Salts", J. PHARM. SCI., vol. 66, 1977, pages 1 - 19, XP002675560, DOI: 10.1002/jps.2600660104
C. A. G. N. MONTALBETTIV FALQUE: "Amide bond formation and peptide coupling", TETRAHEDRON, vol. 61, 2005, pages 10827 - 10852, XP055535483, DOI: 10.1016/j.tet.2005.08.031
ELLMAN, A1 ACC. CHEM. RES., vol. 35, 2002, pages 984 - 995
FRANKLIN A. DAVISBANG-CHI CHEN, CHEM. SOC. REV., vol. 27, 1998, pages 13 - 18
JACOBSEN, M. F.SKRYDSTRUP, T., J. ORG. CHEM., vol. 68, 2003, pages 7122
N. MIYAURAA. SUZUKI: "Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds", CHEM. REV., vol. 957, 1995, pages 2457 - 2483
TANG, T. P.ELLMAN, J. A., J. ORG. CHEM., vol. 64, 1999, pages 12
TANG, T. P.ELLMAN, J. A., J. ORG. CHEM., vol. 67, 2002, pages 7819
TOBIAS G KAPP ET AL: "Integrin modulators: a patent review", EXPERT OPINION ON THERAPEUTIC PATENTS, vol. 23, no. 10, 29 October 2013 (2013-10-29), GB, pages 1273 - 1295, XP055375194, ISSN: 1354-3776, DOI: 10.1517/13543776.2013.818133 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11174228B2 (en) 2018-04-12 2021-11-16 Morphic Therapeutic, Inc. Antagonists of human integrin (α4)(β7)
US11104661B1 (en) 2019-10-16 2021-08-31 Morphic Therapeutic, Inc. Inhibiting human integrin (α-4) (β-7)
US11370773B1 (en) 2019-10-16 2022-06-28 Morphic Therapeutic, Inc. Inhibiting human integrin (alpha-4) (beta-7)
US11866429B2 (en) 2019-10-16 2024-01-09 Chemocentryx, Inc. Heteroaryl-biphenyl amines for the treatment of PD-L1 diseases
WO2023125182A1 (fr) * 2021-12-27 2023-07-06 海思科医药集团股份有限公司 Dérivé d'acide propionique et son utilisation médicale

Also Published As

Publication number Publication date
US11370773B1 (en) 2022-06-28
CN115087444A (zh) 2022-09-20
TWI775182B (zh) 2022-08-21
TWI791304B (zh) 2023-02-01
EP4045039A4 (fr) 2023-12-13
UY38926A (es) 2021-05-31
WO2022081983A1 (fr) 2022-04-21
TW202244040A (zh) 2022-11-16
JP2022542184A (ja) 2022-09-29
TW202126624A (zh) 2021-07-16
CR20220205A (es) 2022-07-22
CL2022000959A1 (es) 2023-04-28
JP7209116B2 (ja) 2023-01-19
DOP2022000081A (es) 2022-07-31
CA3154269A1 (fr) 2021-04-22
EP4228634A1 (fr) 2023-08-23
TW202315868A (zh) 2023-04-16
JP2023036958A (ja) 2023-03-14
KR20230088376A (ko) 2023-06-19
IL292296A (en) 2022-06-01
EP4045039A1 (fr) 2022-08-24
JP2024054296A (ja) 2024-04-16
TW202222793A (zh) 2022-06-16
BR112022007284A2 (pt) 2022-07-05
AR120244A1 (es) 2022-02-09
US11104661B1 (en) 2021-08-31
ZA202203872B (en) 2024-01-31
TWI802477B (zh) 2023-05-11
JP2022548809A (ja) 2022-11-22
CO2022005759A2 (es) 2022-05-20
AU2021361031A1 (en) 2023-06-08
JP7437495B2 (ja) 2024-02-22
WO2021076890A4 (fr) 2021-06-10
US20240174632A1 (en) 2024-05-30
TW202332675A (zh) 2023-08-16
JP7437490B2 (ja) 2024-02-22
KR20220102669A (ko) 2022-07-20
WO2021076890A1 (fr) 2021-04-22
JP2023500437A (ja) 2023-01-06
CN116783161A (zh) 2023-09-19
PE20221829A1 (es) 2022-11-29
JP2024054293A (ja) 2024-04-16
ECSP22038978A (es) 2022-06-30
MX2022004406A (es) 2022-08-25
AU2020366435A1 (en) 2022-04-21
CU20220027A7 (es) 2022-12-12

Similar Documents

Publication Publication Date Title
WO2021076902A1 (fr) INHIBITION DE L'INTÉGRINE α 4 β 7 HUMAINE
CA3133753A1 (fr) Nouveaux inhibiteurs a petites molecules de facteurs de transcription tead
ES2240420T3 (es) Carboxamidas utiles como inhibidores de la proteina de transferencia de trigliceridos microsomicos y de la secrecion de apolipoproteina b.
EP1535922A1 (fr) Derive de pyrrolopyridine et utilisation de ce dernier
JP2022068197A (ja) デュアルｍａｇｌ及びｆａａｈインヒビター
Deutsch et al. Synthesis and pharmacology of site specific cocaine abuse treatment agents: a new synthetic methodology for methylphenidate analogs based on the Blaise reaction
JP2019512550A (ja) エストロゲン受容体ダウンレギュレーターとしての置換インドール化合物
AU2011260411B2 (en) Method for production of F-18 labeled amyloid beta ligands
CA2595400C (fr) Derives de methylphenidate et leurs utilisations pour le traitement de conditions et de maladies angiogeniques
TWI840047B (zh) 人類整合素α4β7之抑制
WO2019163865A1 (fr) Dérivé de dibenzazépine ayant un cycle hétérocyclique contenant de l'azote
Varnes et al. Bicyclo ((aryl) methyl) benzamides as inhibitors of GlyT1
Prante et al. Synthesis and in vitro evaluation of iodine labelled pyrazolo [1, 5‐a] pyridines as highly selective dopamine D4 receptor ligands
SG185783A1 (en) Method for production of f-18 labeled amyloid beta ligands
TWI682928B (zh) 達比加群烷酯衍生物及其製備方法和在藥學上的用途
JP2023540636A (ja) ベンゾ酸素含有複素環化合物及びその医薬用途
JP2023106756A (ja) ボロノフェニルアラニンアミド誘導体

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20804087

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2022509595

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20804087

Country of ref document: EP

Kind code of ref document: A1